*Endocannabinoid Protection and Regulation

Physiological Protection, regulation, nerve protection, migraines,

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PROTECTION AGAINST CELL DEATH

Bari et al 2005

From abstract – Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

Article title:  Cholesterol-dependent modulation of type 1 cannabinoid receptors in nerve cells.

Type 1 cannabinoid receptors (CB1R) are G-protein-coupled receptors that mediate several actions of the endocannabinoid anandamide (N-arachidonoylethanolamine; AEA) in the central nervous system.

… These data demonstrate that, among the proteins of the “endocannabinoid system,” only CB1R and AMT critically depend on membrane cholesterol content. This observation may have important implications for the

role of CB1R in

protecting nerve cells against (endo)cannabinoid-induced apoptosis [cell death].

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Pharmacol Biochem Behav. 2008 Oct;90(4):501-11.

Links

Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures–a short review.

Svízenská I, Dubový P, Sulcová A.

Department of Anatomy, Division of Neuroanatomy, Faculty of Medicine, Masaryk University, Kamenice 3, CZ-625 00 Brno, Czech Republic. isvizen@med.muni.cz

In the last 25 years data has grown exponentially dealing with the discovery of the endocannabinoid system consisting of specific cannabinoid receptors, their endogenous ligands, and enzymatic systems of their biosynthesis and degradation. Progress is being made in the development of novel agonists and antagonists with receptor subtype selectivity which should help in providing a greater understanding of the physiological role of the endocannabinoid system and perhaps also in a broad number of pathologies. This could lead to advances with important therapeutic potential of drugs modulating activity of endocannabinoid system as hypnotics, analgesics, antiemetics, antiasthmatics, antihypertensives, immunomodulatory drugs, antiphlogistics, neuroprotective agents, antiepileptics, agents influencing glaucoma, spasticity and other “movement disorders”, eating disorders, alcohol withdrawal, hepatic fibrosis, bone growth, and atherosclerosis. The aim of this review is to highlight distribution of the CB1 and CB2 receptor subtypes in the nervous system and functional involvement of their specific ligands.

PMID: 18584858 [PubMed – indexed for MEDLINE]

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Cota 2008

J Neuroendocrinol. 2008 May;20 Suppl 1:35-8.

Links

The role of the endocannabinoid system in the regulation of hypothalamic-pituitary-adrenal axis activity.

Cota D.

Department of Psychiatry, Obesity Research Center, Genome Research Institute, University of Cincinnati, Cincinnati, OH 45237, USA. daniela.cota@uc.edu

The endocannabinoid system (ECS) is a recently identified neuromodulatory system, which is involved in several physiological processes and in disease.

For example, the ECS not only represents the biological substrate of marijuana’s effects,

but also is

known to modulate several neuroendocrine axes, including the hypothalamic-pituitary-adrenal (HPA) axis.

Although previous pharmacological studies using plant-derived or synthetic cannabinoids have implied a stimulating action on the HPA axis, more recent findings have led to the conclusion that

an endogenous cannabinoid tone might exist, which is actually inhibiting the release of both adrenocorticotrophic hormone and glucocorticoids.

Studies using mice lacking cannabinoid receptor CB(1) have demonstrated that presence and activity of these receptors is essential for the regulation of HPA axis activity.

Interestingly, the effects of endocannabinoids on the HPA axis are consistent with their neuromodulatory action on brain neurotransmitter systems.

Endocannabinoids have been found to mediate the

nongenomic glucocorticoid-induced inhibition

of the release

of corticotrophin-releasing factor [CRH]

within the paraventricular nucleus of the hypothalamus.

Altogether, these observations suggest that alterations of the endocannabinoid tone might be associated with the development of

stress-related diseases,

including anxiety,

depression and

obesity.

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Steiner & Wotjak 2008

Prog Brain Res. 2008;170:397-432.

Links

Role of the endocannabinoid system in regulation of the hypothalamic-pituitary-adrenocortical axis.

Steiner MA, Wotjak CT.

Max Planck Institute of Psychiatry, Neuroplasticity Group, Kraepelinstrasse, Munich, Germany.

The endocannabinoid system has been recognized as a major neuromodulatory system,

which functions to maintain brain homoeostasis.

Endocannabinoids

are synthesized and released

from the postsynapse and

act as retrograde neuronal messengers,

which bind to cannabinoid type 1 receptors at the presynapse.

Here, they inhibit the release of neurotransmitters, including glutamate and GABA.

By these means, endocannabinoids

control the activation of various neuronal circuits

including those involved

in neuroendocrine stress processing.

Accordingly, exogenous cannabinoids such as the major active component of marijuana, Delta(9)-tetrahydrocannabinol, have long been known to

activate the major neuroendocrine stress response system of mammals, the hypothalamic-pituitary-adrenocortical (HPA) axis.

However, the function of the endocannabinoid system in the regulation of stress hormone secretion has only recently begun to be understood. It is the focus of the present review to provide the reader with an overview of our current knowledge of

the role of endocannabinoid signalling in HPA axis regulation

under basal as well as under stressful conditions. This includes the specific sites of action, potential underlying neuronal pathways and interactions between behavioural and neuroendocrine stress coping. Furthermore, the potential role of HPA axis activity dysregulations, caused by deficits in the endocannabinoid system, for the pathophysiology of psychiatric diseases is discussed.

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Coddington et al 2007

Prostaglandins Leukot Essent Fatty Acids. 2002 Feb-Mar;66(2-3):301-7.

Links

The role of endocannabinoids in the hypothalamic regulation of visceral function.

Wenger T, Moldrich G.

Department of Human Morphology and Developmental Embryology, Semmelweis University Budapest, Tüzoltó u.58, PO Box 95, H-1450 Budapest, Hungary. wenger@ana2.sote.hu

The hypothalamus plays an important role in the regulation of several visceral processes, including

food intake,

thermoregulation and

control of anterior pituitary secretion.

Endogenous cannabinoids and CB(1) cannabinoid receptors have been found in the hypothalamus. In the present review, we would like to clarify the role of the endocannabinoid system in the regulation of the above-mentioned visceral functions. There is historical support for the role of marihuana (i.e. exogenous cannabinoids) in the regulation of appetite. Endocannabinoids also stimulate food intake. Furthermore, the specific CB(1) receptor antagonist SR141716 reduces food intake. Leptin treatment decreases endocannabinoid levels in normal rats and ob/ob mice. These findings provide evidence for the role of the hypothalamic endocannabinoid system in food intake and appetite regulation.

Cannabinoids can change body temperature

in a dose-dependent manner.

High doses cause hypothermia while

low doses cause hyperthermia.

Cannabinoid administration decreases heat production.

Role in immune system and inflammation

It seems that the effects of cannabinoids on thermoregulation is exerted by altering some neurochemical mediator effects at both the presynaptic and postsynaptic level.

THC and endocannabinoids have

mainly inhibitory effects on the regulation of reproduction.

Administration of anandamide (AEA) decreases serum luteinizing hormone (LH) and prolactin (PRL) levels.

…….AEA causes a prolongation of pregnancy in rats and

temporarily inhibits the postnatal development

of the hypothalamo-pituitary axis in offspring.

The action of AEA on the reproductory parameters occurs at both the hypothalamic and pituitary level.

……CB(1) receptors have also been found in the anterior pituitary. Further, LH levels in CB(1) receptor-inactivated mice were decreased compared with wild-type mice. Taken together, all these observations suggest that the endocannabinoid system is playing an important part in the regulation of the mentioned visceral functions and it provides the bases for further applications of cannabinoid receptor agonists and/or antagonists in visceral diseases regulated by the hypothalamus.

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Bahr 2006

Expert Opin Investig Drugs. 2006 Apr;15(4):351-65.

Links

Targeting the endocannabinoid system in treating brain disorders.

Bahr BA, Karanian DA, Makanji SS, Makriyannis A.

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA. Bahr@uconn.edu

Recent cannabinoid research has a primary focus on developing therapeutics against human diseases. Many studies on cannabinoids indicate important progress for protection against several neurodegenerative disorders.

…Agonists of cannabinoid receptors activate signalling pathways in the brain that are linked to neuronal repair and cell maintenance, and ….endogenous ligands can also activate neuroprotective responses.

These endocannabinoids are bioactive fatty acid amides and esters that are synthesised in the brain and include arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol.

Endocannabinoids are released in response to pathogenic events,

thus representing a potential compensatory repair mechanism.

Enhancing this on-demand action of endocannabinoids is a strategy with which to promote endogenous repair signalling.

For such enhancement, considerable work has gone into modulating the availability of endocannabinoids by blocking the processes of their deactivation. ……….The targets include the anandamide-hydrolysing enzyme fatty acid amide hydrolase,

…………the carrier-mediated anandamide transport system

……..and 2-arachidonoyl glycerol-deactivating enzyme monoacylglycerol lipase.

The activity of endocannabinoids is terminated through transport and degradation and, accordingly,

……..selective inhibitors of these processes effectively exploit the protective nature of cannabinergic responses.

This review highlights recent studies implicating the endocannabinoid system in neuroprotection against different disorders of the CNS.

See also:

Curr Mol Med. 2006 Sep;6(6):677-84.

Links

Cannabinoid drugs and enhancement of endocannabinoid responses: strategies for a wide array of disease states.

Karanian DA, Bahr BA.

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092, USA. david.karanian@uconn.edu

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Borner et al 2008

Mol Pharmacol. 2008 Mar;73(3):1013-9. Epub 2007 Dec 21.

Links

Analysis of promoter regions regulating basal and interleukin-4-inducible expression of the human CB1 receptor gene in T lymphocytes.

Börner C, Bedini A, Höllt V, Kraus J.

Department of Pharmacology and Toxicology, Magdeburg University, 44 Leipzigerstrasse, 39120 Magdeburg, Germany

The majority of effects of cannabinoids are mediated by the two receptors CB1 and CB2. In addition to neuronal cells, CB1 receptors are expressed in T lymphocytes, in which they are involved in cannabinoid-induced T helper cell biasing. Although basally expressed only weakly in T cells, CB1 receptors are up-regulated in these cells by stimuli such as cannabinoids themselves. This effect is mediated by interleukin-4. In this study, we investigated basal and interleukin-4-inducible expression of the CB1 gene in T lymphocytes. In a promoter analysis, two regions [nucleotides (nts) -3086 to -2490 and nts -1950 to -1653] were identified, which suppress basal transcription of the gene in Jurkat T cells, whereas the region between nts -648 and -559 enhanced basal CB1 transcription. Interleukin-4 markedly induced transcription of CB1 in Jurkat cells and primary human T cells. Experiments using transcription factor decoy oligonucleotides demonstrated that STAT6 mediates regulation of the gene by interleukin-4. Using reporter gene assays and the transcription factor decoy oligonucleotide approach, a binding site for STAT6 was identified at nt -2769 on the human CB1 gene promoter. Interleukin-4 also caused up-regulation of functional CB1 receptor proteins. In interleukin-4 pretreated, but not in naive Jurkat cells, the CB1 agonist R(+)-methanandamide caused a significant inhibition of forskolin-induced cAMP formation. This effect was blocked by the CB1-selective antagonists N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) and 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-mo rpholinyl-1H-pyrazole-3-carboxamide (AM281). Taken together, these data show

that CB1 receptors are expressed and up-regulated by interleukin-4 in T lymphocytes, which enables CB1-mediated communication to cells of other systems, such as neuronal cells.

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Karanian & Bahr 2006

Curr Mol Med. 2006 Sep;6(6):677-84.

Links

Cannabinoid drugs and enhancement of endocannabinoid responses: strategies for a wide array of disease states.

Karanian DA, Bahr BA.

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092, USA. david.karanian@uconn.edu

The endogenous cannabinoid system

….has revealed potential avenues to treat many disease states.

…….Medicinal indications of cannabinoid drugs including compounds that result in enhanced endocannabinoid responses (EER) have expanded markedly in recent years.

The wide range of indications covers

..chemotherapy complications,

..tumor growth,

..addiction,

..pain,

..multiple sclerosis,

..glaucoma,

..inflammation,

..eating disorders,

…age-related neurodegenerative disorders, as well as

…epileptic seizures,

…traumatic brain injury,

..cerebral ischemia, and

..other excitotoxic insults.

Indeed, a great effort has led to the discovery of agents that selectively

…activate the cannabinoid system

….or that enhance the endogenous pathways of cannabinergic signaling.

The endocannabinoid system is comprised of three primary components: (i) cannabinoid receptors,

(ii) endocannabinoid transport system, and

(iii) hydrolysis enzymes that break down the endogenous ligands.

Two known endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), are lipid molecules

….that are greatly elevated in response to a variety of pathological events.

This increase in endocannabinoid levels

….is suggested to be part of an on-demand compensatory response.

Furthermore, activation of signaling pathways mediated by the endogenous cannabinoid system promotes repair and cell survival.

Similar cell maintenance effects are elicited by

….EER through inhibitors of the endocannabinoid deactivation processes (i.e., internalization and hydrolysis).

The therapeutic potential of the endocannabinoid system has yet to be fully determined, and the number of medical maladies that may be treated will likely continue to grow. This review will underline studies that demonstrate medicinal applications for agents that influence the endocannabinoid system.

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Kyrou, Valsamakis & Tsigos 2006

Ann N Y Acad Sci. 2006 Nov;1083:270-305.

Links

The endocannabinoid system as a target for the treatment of visceral obesity and metabolic syndrome.

Kyrou I, Valsamakis G, Tsigos C.

Endocrinology, Metabolism and Diabetes Unit, Evgenidion Hospital, Athens University Medical School, Athens 115 28, Greece.

The endogenous cannabinoid system is a novel, remarkably elaborate physiological signaling system,

comprising the recently identified endogenous cannabinoid ligands,

their corresponding selective receptors, and the

machinery of proteins and enzymes that is involved in their biosynthesis, release, transport, and degradation.

This system extends widely in both the central nervous system (CNS) and the periphery and exhibits a variety of actions implicated in vital functions (e.g., behavioral, antinociceptive, neuroprotective, immunosuppressive, cardiovascular, and metabolic).

Particular interest has been focused on the

apparent participation

of endocannabinoids

in metabolic homeostasis

by modulating the activity of CNS circuits

that control food intake and energy expenditure,

the neuroendocrine response of the stress system, and the metabolic functions of crucial peripheral tissues, such as the adipose tissue, the

gastrointestinal tract, the

liver, and the

skeletal muscles. [and bones]

These effects are predominantly CB(1) receptor mediated and, thus, selective antagonists of this receptor subtype are being vigorously investigated as potential therapeutic agents for the treatment of various metabolic derangements (e.g., obesity, insulin resistance, dyslipidemia, and metabolic syndrome). The first selective CB(1) receptor antagonist, rimonabant, has already successfully completed phase III clinical trials as adjunctive obesity treatment, with significant improvements in several associated metabolic and cardiovascular risk factors that led to the recent approval of its clinical use by the Food and Drug Administration.

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Lamontagne et al 2006

Arch Mal Coeur Vaiss. 2006 Mar;99(3):242-6.

Links

The endogenous cardiac cannabinoid system: a new protective mechanism against myocardial ischemia.

Lamontagne D, Lépicier P, Lagneux C, Bouchard JF.

Faculté de pharmacie, Université de Montréal, QC, Canada. daniel.lamontagne@umontreal.ca

The pharmacological (and recreational) effects of cannabis have been known for centuries. ……….However, it is only recently that one has identified two subtypes of G-protein-coupled receptors, namely CB1 and CB2-receptors,

……….which mediate the numerous effects of delta9-tetrahydrocannabinol

……..and other cannabinoids.

Logically, the existence of cannabinoid-receptors implies that endogenous ligands [a molecule that binds to a specific site on a protein]

…….for these receptors (endocannabinoids) exist

…..and exert a physiological role.

Hence, arachidonoylethanolamide (anandamide) and sn-2 arachidonoylglycerol, the first two endocannabinoids identified,

are formed from plasma membrane phospholipids

…………and act as CB1 and/or CB2 agonists.

The presence of both CB1 and CB2-receptors in the rat heart is noteworthy. This

endogenous cardiac cannabinoid system

is involved in several phenomena associated with cardioprotective effects.

….The reduction in infarct size following myocardial ischemia… is abolished in the presence of a CB2-receptor antagonist.

…..Endocannabinoids and synthetic cannabinoids, the latter through either CB1 or CB2-receptors, exert direct cardioprotective effects in rat isolated hearts.

The ability of cannabinoids to reduce infarct [the area of heart tissue permanently damaged by an inadequate supply of oxygen] size has been confirmed in vivo in anesthetized mice and rats.

…..This latter effect appears to be mediated through CB2-receptors.

Thus, the endogenous cardiac cannabinoid system,

……through activation of CB2-receptors,

…..appears to be an important mechanism of protection against myocardial ischemia. [insufficient blood flow to part of the heart]

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Mukhopadhyay et al 2007

J Am Coll Cardiol. 2007 Aug 7;50(6):528-36. Epub 2007 Jul 23.

Links

Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity.

Mukhopadhyay P, Bátkai S, Rajesh M, Czifra N, Harvey-White J, Haskó G, Zsengeller Z, Gerard NP, Liaudet L, Kunos G, Pacher P.

Laboratory of Physiological Studies, NIH/NIAAA, Bethesda, Maryland 20892, USA.

OBJECTIVES: We aimed to explore the effects of pharmacologic inhibition of cannabinoid-1 (CB1) receptor in in vivo and in vitro models of doxorubicin (DOX)-induced cardiotoxicity.

BACKGROUND: Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is limited because of the risk of severe cardiotoxicity.

………. Endocannabinoids mediate cardiodepressive effects through CB1 receptors in various pathophysiological conditions,

………and these effects can be reversed by CB1 antagonists.

METHODS: Left ventricular function was measured by Millar pressure-volume system. Apoptosis markers, CB1/CB2 receptor expression, and endocannabinoid levels were determined by immunohistochemistry, Western blot, reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, flow cytometry, fluorescent microscopy, and liquid chromatography/in-line mass spectrometry techniques. RESULTS: Five days after the administration of a single dose of DOX (20 mg/kg intraperitoneally) to mice, left ventricular systolic pressure, maximum first derivative of ventricular pressure with respect to time (+dP/dt), stroke work, ejection fraction, cardiac output, and load-independent indexes of contractility (end-systolic pressure-volume relation, preload-recruitable stroke work, dP/dt-end-diastolic volume relation) were significantly depressed, and the myocardial level of the endocannabinoid anandamide (but not CB1/CB2 receptor expression) was elevated compared with vehicle-treated control mice. Treatment with the CB1 antagonists rimonabant or AM281 markedly improved cardiac dysfunction and reduced DOX-induced apoptosis in the myocardium.

Doxorubicin also decreased cell viability and induced apoptosis in the H9c2 myocardial cell line measured by flow cytometry and fluorescent microscopy, …………which were prevented by the preincubation of the cells with either CB1 antagonist,

……….but not with CB1 and CB2 agonists and CB2 antagonists.

CONCLUSIONS: These data suggest that CB1 antagonists may represent a new cardioprotective strategy against DOX-induced cardiotoxicity.

What’s that song, “Doctor, my heart has seen……”??  by the Eagles, maybe?  Well, I’m sure the song says, “Doctor, my eyes have seen…..”  whatever it is they have seen.

So endogenous cannabinoids protect the heart!  Interesting.  And head up the motor squad.

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Clin Cornerstone. 2005;7(2-3):17-26.

Links

The endocannabinoid system: a new approach to control cardiovascular disease.

Cannon CP.

Harvard Medical School, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

The endocannabinoid (EC) system consists of 2 types of G-protein-coupled cannabinoid receptors–cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2)–and their natural ligands. The EC system plays a key role in the regulation of food intake and fat accumulation, as well as glucose and lipid metabolism. When overactivated, the EC system triggers dyslipidemia, thrombotic and inflammatory states, and insulin resistance. Blocking CB1 receptors centrally and peripherally in adipose tissue can help normalize an overactivated EC system. CB1 blockade helps regulate food intake and adipose tissue metabolism, contributing to improved insulin sensitivity and other features of the metabolic syndrome. Visceral adipose tissue is most closely associated with the metabolic syndrome, which is a constellation of conditions that place people at high risk for coronary artery disease. Targeting the EC system represents a new approach to treating visceral obesity and reducing cardiovascular risk factors.

PMID: 16473257 [PubMed – indexed for MEDLINE

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Micale, Mazzola & Drago 2007

Pharmacol Res. 2007 Nov;56(5):382-92. Epub 2007 Sep 11.

Links

Endocannabinoids and neurodegenerative diseases.

Micale V, Mazzola C, Drago F.

Department of Experimental and Clinical Pharmacology, University of Catania, Medical School, Catania, Italy.

The cannabinoid CB1 and CB2 receptors,

…..the endogenous endocannabinoid (EC) ligands anandamide (AEA) and 2-arachidonylethanolamide,

…..and the degradative enzymes fatty acid amide hydrolase (FAAH)

…..and monoglyceride lipase (ML) are key elements of the EC system

implicated in different physiological functions including cognition, motor activity and immune responses.

Thus, both the possible

neuroprotective role of ECs and their modulating action on neurotransmitter systems

affected in several neurodegenerative diseases such as Alzheimer’s disease (AD), Huntington’s disease (HD) and multiple sclerosis (MS) are currently under investigation.

Accumulating data show an

…..unbalance in the EC system (i.e. decrease of neuronal cannabinoid CB1 receptors, increase of glial cannabinoid CB2 receptors and over-expression of FAAH in astrocytes)

……. in experimental models of AD as well as in post-mortem brain tissue of AD patients, suggesting its possible role in inflammatory processes and in neuroprotection.

However, the

mechanisms of the EC modulation of immune response

are not fully understood. By contrast, in HD

….a reduced EC signaling,

…given both by the loss of cannabinoid CB1 receptors and decrease of ECs in brain structures involved in movement control as basal ganglia, has been well documented in preclinical and clinical studies. Thus, in the present review we discuss recent data concerning the role of the EC system in the pathophysiology of AD and HD, two neurodegenerative diseases characterized by cognitive deficit and motor impairment, respectively. We focus on the effects of compounds modulating the EC system (agonists/antagonists of cannabinoid CB1 and CB2 receptors, or inhibitors of ECs metabolism processes) on the symptoms and/or progression of neurodegenerative diseases.

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Kaczocha et al 2006

J Biol Chem. 2006 Apr 7;281(14):9066-75. Epub 2006 Feb 6.

Links

Anandamide uptake is consistent with rate-limited diffusion and is regulated by the degree of its hydrolysis by fatty acid amide hydrolase.

Kaczocha M, Hermann A, Glaser ST, Bojesen IN, Deutsch DG.

Department of Biochemistry and Cell Biology, State University of New York at Stony Brook, Stony Brook, New York 11794-5215, USA.

The uptake of arachidonoyl ethanolamide (anandamide, AEA) [an endogenous cannabinoid substance]

….in rat basophilic leukemia cells (RBL-2H3)

…Longer incubation times illuminate downstream events that drive AEA uptake. …. with appreciable inhibition of AEA accumulation correlating with partial inhibition of AEA hydrolysis.

…… weak inhibition of FAAH can have a pronounced effect upon AEA uptake

This strongly suggests that the target of UCM707, VDM11, OMDM2, and AM1172 is not a transporter at the plasma membrane but rather FAAH, or an

uncharacterized intracellular component that delivers AEA to FAAH.

This system is therefore unique among

…..neuro/immune modulators

….because AEA, an uncharged hydrophobic molecule,

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Molina-Holgado et al 2002

J Neurosci. 2002 Nov 15;22(22):9742-53.

Links

Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling.

Molina-Holgado E, Vela JM, Arévalo-Martín A, Almazán G, Molina-Holgado F, Borrell J, Guaza C.

Department of Neural Plasticity, Cajal Institute, Consejo Superior de Investigaciones Cientificas, 28002 Madrid, Spain. eduardomolina@cajal.csic.es

Cannabinoids exert pleiotropic [a single gene determines more than one phenotype for an organism] actions in the CNS,

…. including the inhibition of inflammatory responses

…..and the enhancement of neuronal survival after injury.

Although cannabinoid receptors are distributed widely in brain, their presence has not been investigated previously in oligodendrocytes [glial cells that produce and support the myelin sheath, in the CNS].

This study examined the expression of cannabinoid type 1 (CB1) receptors in rat oligodendrocytes in vivo and in culture and explored their biological function.

Expression of CB1 receptors by oligodendrocytes was demonstrated immunocytochemically in postnatal and in adult white matter as well as in oligodendrocyte cultures. Reverse transcription-PCR and Western blotting further confirmed the presence of CB1 receptors.

Oligodendrocyte progenitors undergo apoptosis with the withdrawal of trophic support, as determined by TUNEL assay and caspase-3 activation,

……and both the selective CB1 agonist arachidonyl-2′-chloroethylamide/(all Z)-N-(2-cycloethyl)-5,8,11,14-eicosatetraenamide (ACEA) and the nonselective cannabinoid agonists HU210 and (+)-Win-55212-2

……enhanced cell survival.

To investigate intracellular signaling involved in cannabinoid protection, ……we focused on the phosphatidylinositol-3 kinase (PI3K)/Akt pathway.

……HU210, (+)-Win-55212-2, and ACEA elicited a time-dependent phosphorylation of Akt. Pertussis toxin abolished Akt activation, indicating the involvement of G(i)/G(o)-protein-coupled receptors.

These data identify oligodendrocytes as potential targets of cannabinoid action in the CNS.

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IMPORTANT – GLUTAMATE TOXICITY PROTECTION

van der Stelt et al 2003

Neurotox Res. 2003;5(3):183-200.

Links

Biosynthesis of endocannabinoids and their modes of action in neurodegenerative diseases.

van der Stelt M, Hansen HH, Veldhuis WB, Bär PR, Nicolay K, Veldink GA, Vliegenthart JF, Hansen HS.

Department of Bio-organic Chemistry, Bijvoet Center for Biomolecular Science, Padualaan 8, NL-3584 CH Utrecht University, Utrecht, The Netherlands

Endocannabinoids are thought to function as retrograde messengers, ….which modulate neurotransmitter release

…..by activating presynaptic cannabinoid receptors.

Anandamide and 2-arachidonoylglycerol (2-AG) are the two best studied endogenous lipids which can act as endocannabinoids.

…….Together with the proteins responsible for their biosynthesis, inactivation and the cannabinoid receptors, these lipids constitute the endocannabinoid system.

This system is proposed to be involved in various neurodegenerative diseases such as Parkinson’s and Huntington’s diseases as well as Multiple Sclerosis.

……… It has been demonstrated that the endocannabinoid system

can protect neurons against

glutamate excitotoxicity

and acute neuronal damage

in both in vitro and in vivo models. In this paper we review the data concerning the involvement of the

endocannabinoid system in neurodegenerative diseases in which neuronal cell death may be elicited by excitotoxicity.

We focus on the biosynthesis of endocannabinoids and on their modes of action in animal models of these neurodegenerative diseases.

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Mini Rev Med Chem. 2009 Apr;9(4):448-62.

Links

Endocannabinoid system: emerging role from neurodevelopment to neurodegeneration.

Basavarajappa BS, Nixon RA, Arancio O.

Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, NY 10962, USA. Basavaraj@nki.rfmh.org

Mol Neurobiol. 2002 Oct-Dec;26(2-3):317-46.

Links

Acute neuronal injury, excitotoxicity, and the endocannabinoid system.

van der Stelt M, Veldhuis WB, Maccarrone M, Bär PR, Nicolay K, Veldink GA, Di Marzo V, Vliegenthart JF.

Department of Bio-Organic Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, The Netherlands.

Curr Pharm Des. 2008;14(23):2279-88.

Links

Mechanisms of control of neuron survival by the endocannabinoid system.

Galve-Roperh I, Aguado T, Palazuelos J, Guzmán M.

Department of Biochemistry and Molecular Biology I, School of Biology, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Complutense University, 28040 Madrid, Spain. igr@quim.ucm.es

Ital J Biochem. 2006 Sep-Dec;55(3-4):283-9.

Links

The endocannabinoid system in neurodegeneration.

Battista N, Fezza F, Finazzi-Agrò A, Maccarrone M.

Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

Expert Opin Investig Drugs. 2006 Apr;15(4):351-65.

Links

Targeting the endocannabinoid system in treating brain disorders.

Bahr BA, Karanian DA, Makanji SS, Makriyannis A.

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA. Bahr@uconn.edu

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Centonze, Battistini & Maccarrone 2008

Curr Pharm Des. 2008;14(23):2370-42.

Links

The endocannabinoid system in peripheral lymphocytes as a mirror of neuroinflammatory diseases.

Centonze D, Battistini L, Maccarrone M.

Department of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, 64100 Teramo, Italy. mmaccarrone@unite.it.

During immuno-mediated attack of the brain,

activation of endocannabinoids represents a protective mechanism,

aimed at reducing both neurodegenerative and inflammatory damage

through various and partially converging mechanisms

that involve neuronal and immune cells.

Here, we review the main alterations of the endocannabinoid system (ECS) within the central nervous system and in peripheral blood mononuclear cells, in order to discuss the intriguing observation that

elements of the peripheral ECS mirror central dysfunctions of endocannabinoid signaling.

As a consequence, elements of blood ECS might serve as novel, non-invasive diagnostic tools of several neurological disorders, and targeting the ECS might be useful for therapeutic purposes. In addition, we discuss the appealing working hypothesis that

the presence of type-1 cannabinoid receptors on the luminal side,

and that of type-2 cannabinoid receptors on the abluminal side

of the blood-brain barrier,

could drive a unidirectional transport of AEA in the luminal –> abluminal direction (i.e., from blood to brain), thus implying that blood may be a reservoir of AEA for the brain.

On this basis, it can be expected that

an unbalance of the endogenous tone of AEA in the blood may sustain a similar unbalance of its level within the brain,

as demonstrated in

Huntington’s disease,

Parkinson’s disease,

multiple sclerosis,

attention-deficit/hyperactivity disorder,

schizophrenia,

depression and

headache.

See also:

Brain. 2007 Oct;130(Pt 10):2543-53. Epub 2007 Jul 11.

Links

The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis.

Centonze D, Bari M, Rossi S, Prosperetti C, Furlan R, Fezza F, De Chiara V, Battistini L, Bernardi G, Bernardini S, Martino G, Maccarrone M.

Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Rome, Italy. centonze@uniroma2.it

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Maresz et al 2007

Nat Med. 2007 Apr;13(4):492-7. Epub 2007 Apr 1.

Links

Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells.

Maresz K, Pryce G, Ponomarev ED, Marsicano G, Croxford JL, Shriver LP, Ledent C, Cheng X, Carrier EJ, Mann MK, Giovannoni G, Pertwee RG, Yamamura T, Buckley NE, Hillard CJ, Lutz B, Baker D, Dittel BN.

BloodCenter of Wisconsin, Blood Research Institute, Milwaukee, Wisconsin 53226, USA.

The cannabinoid system is immunomodulatory and has been targeted as a treatment for the central nervous system (CNS) autoimmune disease multiple sclerosis. Using an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we investigated the role of the CB(1) and CB(2) cannabinoid receptors in regulating CNS autoimmunity.

We found that CB(1) receptor expression by neurons, but not T cells, was required for cannabinoid-mediated EAE suppression.

In contrast, CB(2) receptor expression by encephalitogenic T cells was critical for controlling inflammation associated with EAE.

CB(2)-deficient T cells in the CNS during EAE exhibited reduced levels of apoptosis, a higher rate of proliferation and increased production of inflammatory cytokines, resulting in severe clinical disease. Together, our results demonstrate that the

cannabinoid system within the CNS

plays a critical role in regulating autoimmune inflammation,

with the CNS directly suppressing T-cell effector function via the CB(2) receptor. What does this mean?

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Borner, Hollt & Kraus 2007

Neuroimmunomodulation. 2007;14(6):281-6. Epub 2008 Feb 21.

Links

Activation of human T cells induces upregulation of cannabinoid receptor type 1 transcription.

Börner C, Höllt V, Kraus J.

Department of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany.

OBJECTIVE: Effects of cannabinoids are mediated by CB1 and CB2 receptors. In addition to neuronal effects,

cannabinoids are potent modulators of immune functions.

In this report, we investigated whether the transcription of these receptors is regulated after activation of T lymphocytes

METHODS: CB1- and CB2-specific mRNA of primary human peripheral blood T cells and cells of the human T cell line Jurkat was measured by quantitative real-time RT-PCR in response to CD3/28. Using the decoy oligonucleotide approach, transcription factors involved in the regulation were determined. A promoter analysis was performed using transient transfection of chloramphenicol acetyl transferase reporter gene constructs in Jurkat cells. RESULTS: Activation of human T cells caused an induction of CB1 mRNA expression in primary human T cells (8-fold) and Jurkat cells (29-fold). In contrast, CB2 transcription was not regulated. The CD3/28-mediated upregulation of CB1 involves the transcription factors AP-1, NF kappaB and NFAT. Furthermore, 2,490 bp of the CB1 promoter mediated inducibility in response to CD3/28.

CONCLUSIONS: The

upregulation of CB1

in activated T cells,

together with the

constitutive

expression of CB2,

enables cellular responses

to cannabinoids

mediated by both receptor subtypes.

It may thus contribute to the understanding of the

various modulatory effects of cannabinoids

on activated T cells.

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Newton et al 2008

J Neuroimmune Pharmacol. 2009 Mar;4(1):92-102. Epub 2008 Sep 16.

Links

CB(1) and CB(2) cannabinoid receptors mediate different aspects of delta-9-tetrahydrocannabinol (THC)-induced T helper cell shift following immune activation by Legionella pneumophila infection.

Newton CA, Chou PJ, Perkins I, Klein TW.

Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA. cnewton@health.usf.edu

Legionella pneumophila infection of mice induces proinflammatory cytokines and Th1 immunity as well as rapid increases in serum levels of IL-12 and IFNgamma and splenic IL-12Rbeta2 expression. Delta-9-tetrahydrocannabinol

(THC) treatment prior to infection causes a shift from Th1 to Th2 immunity

and here we demonstrate that CB(1) and CB(2) cannabinoid receptors mediate different aspects of the shift.

Using cannabinoid receptor antagonists and cannabinoid receptor gene deficient mice (CB(1) (-/-) and CB(2) (-/-)), we showed that both CB(1) and CB(2) receptors were involved in the THC-induced attenuation of serum IL-12 and IFNgamma. IFNgamma production is dependent upon signaling through IL-12Rbeta2 (beta2) and THC treatment suppressed splenic beta2 message; moreover, this effect was CB(1) but not CB(2)-dependent from studies with receptor antagonists and CB1(-/-) and CB2(-/-) mice. Furthermore, observed increases in IL-4 induced by THC, were not involved in the drug effect on beta2 from studies with IL-4 deficient mice. The GATA-3 transcription factor is necessary for IL-4 production and is selectively expressed in Th2 cells. GATA-3 message levels were elevated in spleens of THC-treated and L. pneumophila-infected mice and the effect was shown to be CB(2) but not CB(1)-dependent. Furthermore, GATA-3 regulatory factors were modulated in that Notch ligand Delta4 mRNA was decreased and Jagged1 increased by THC also in a CB2-dependent manner and splenic NFkappaB p65 was increased. Together, these results indicate that CB(1) and CB(2) mediate the THC-induced shift in T helper activity in L. pneumophila-infected mice, with

……..CB(1) involved in suppressing IL-12Rbeta2 and

…….CB(2) involved in enhancing GATA-3.

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Singh & Budhiraja 2006

Methods Find Exp Clin Pharmacol. 2006 Apr;28(3):177-83.

Links

Therapeutic potential of cannabinoid receptor ligands: current status.

Singh J, Budhiraja S.

Department of Pharmacology, Pt. B.D. Sharma PGIMS, Rohtak, Haryana, India.

There are at least two types of cannabinoid receptors, CB1 also named CNR1 and CB2 also named CNR2, both coupled to G proteins.

………CB1 receptors exist primarily on central and peripheral neurons.

………CB2 receptors are present mainly on immune cells.

Endogenous agonists for cannabinoid receptors (endocannabinoids) have also been discovered,

….the most important being arachidonoyl ethanolamide (anandamide),

……2-arachidonoyl glycerol (2-AG), and

…..2-archidonyl glyceryl ether.

Following their release, endocannabinoids are removed from the extracellular space and then degraded by intracellular enzymic hydrolysis.

CB1/CB2 agonists are already used clinically as

antiemetic [drugs are drugs used to combat nausea and vomiting] or to

….stimulate appetite. Potential therapeutic uses of cannabinoid receptor agonists include the ….management of multiple sclerosis,

….spinal cord injury,

….pain,

….inflammatory disorders,

….glaucoma,

….bronchial asthma,

….vasodilatation that accompanies advanced cirrhosis, and

….cancer.

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Pertwee 2005

Handb Exp Pharmacol. 2005;(168):1-51.

Links

Pharmacological actions of cannabinoids.

Pertwee RG.

School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. rgp@abdn.ac.uk

Mammalian tissues express at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled.

………CB1 receptors are expressed predominantly at nerve terminals where they mediate inhibition of transmitter release.

……….CB2 receptors are found mainly on immune cells, one of their roles being to modulate cytokine release.

Endogenous ligands for these receptors (endocannabinoids) also exist.

These are all eicosanoids;

…..prominent examples include arachidonoylethanolamide (anandamide) and 2-arachidonoyl glycerol.

These discoveries have led to the development of CB1- and CB2-selective agonists and antagonists and of bioassays for characterizing such ligands. ……..Cannabinoid receptor antagonists include the CB1-selective SR141716A, AM251, AM281 and LY320135, and the CB2-selective SR144528 and AM630. ………..These all behave as inverse agonists,

……..one indication that CB1 and CB2 receptors can exist in a constitutively [at a constant rate regardless of physiological demand] active state.

Neutral cannabinoid receptor antagonists that seem to lack inverse agonist properties have recently also been developed.

……As well as acting on CB1 and CB2 receptors, there is convincing evidence that anandamide can activate transient receptor potential vanilloid type 1 (TRPV1) receptors.

Certain cannabinoids also appear to have

…non-CB1,

…non-CB2,

…non-TRPV1 targets, for example

CB2-like receptors that can mediate antinociception and

…. “abnormal-cannabidiol” receptors that mediate vasorelaxation and promote microglial cell [macrophage-lineage cell that is derived from bone marrow and is present in the central nervous system] migration.

There is evidence too for

………. TRPV1-like receptors on glutamatergic neurons,

…….for alpha2-adrenoceptor-like (imidazoline) receptors at sympathetic nerve terminals,

………for novel G protein-coupled receptors for R-(+)-WIN55212

……..and anandamide in the brain and spinal cord,

……..for novel receptors for delta9-tetrahydrocannabinol

……..and cannabinol on perivascular sensory nerves

……..and for novel anandamide receptors in the gastro-intestinal tract.

The presence of allosteric [inhibition or activation of an enzyme by a small regulatory molecule that interacts at a site (allosteric site)] sites for cannabinoids on various ion channels and non-cannabinoid receptors has also been proposed. In addition, more information is beginning to emerge about the pharmacological actions of the

non-psychoactive plant cannabinoid, cannabidiol. These recent advances in cannabinoid pharmacology are all discussed in this review.

See also:

Interactions of cannabidiol with endocannabinoid signalling in hippocampal tissue.

Ryan D, Drysdale AJ, Pertwee RG, Platt B.

Eur J Neurosci. 2007 Apr;25(7):2093-102.

PMID: 17419758 [PubMed – indexed for MEDLINE]

Related Articles

Cannabinoid pharmacology: the first 66 years.

Pertwee RG.

Br J Pharmacol. 2006 Jan;147 Suppl 1:S163-71.

PMID: 16402100 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

The endogenous cannabinoid anandamide activates vanilloid receptors in the rat hippocampal slice.

Al-Hayani A, Wease KN, Ross RA, Pertwee RG, Davies SN.

Neuropharmacology. 2001 Dec;41(8):1000-5.

PMID: 11747904 [PubMed – indexed for MEDLINE]

Related Articles

Pharmacological actions and therapeutic uses of cannabis and cannabinoids.

Kumar RN, Chambers WA, Pertwee RG.

Anaesthesia. 2001 Nov;56(11):1059-68. Review.

PMID: 11703238 [PubMed – indexed for MEDLINE]

Related Articles

Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications for antinociception.

Ross RA, Coutts AA, McFarlane SM, Anavi-Goffer S, Irving AJ, Pertwee RG, MacEwan DJ, Scott RH.

Neuropharmacology. 2001;40(2):221-32.

PMID: 11114401 [PubMed – indexed for MEDLINE]

Related Articles

Pharmacology of cannabinoid receptor ligands.

Pertwee RG.

Curr Med Chem. 1999 Aug;6(8):635-64. Review.

PMID: 10469884 [PubMed – indexed for MEDLINE]

Related Articles

Pharmacological characterization of three novel cannabinoid receptor agonists in the mouse isolated vas deferens.

Pertwee RG, Griffin G, Lainton JA, Huffman JW.

Eur J Pharmacol. 1995 Sep 25;284(3):241-7.

PMID: 8666005 [PubMed – indexed for MEDLINE]

Related Articles

Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism.

Paton WD, Pertwee RG.

Br J Pharmacol. 1972 Feb;44(2):250-61.

PMID: 4668592 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC

Pertwee 2005 b

Life Sci. 2005 Feb 4;76(12):1307-24. Epub 2004 Dec 8.

Links

Inverse agonism and neutral antagonism at cannabinoid CB1 receptors.

Pertwee RG.

School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. rgp@abdn.ac.uk

There are at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled.

……….CB1 receptors are expressed predominantly at nerve terminals and mediate inhibition of transmitter release whereas

………..CB2 receptors are found mainly on immune cells, one of their roles being to modulate cytokine release.

Endogenous cannabinoid receptor agonists also exist and these “endocannabinoids” together with their receptors constitute the “endocannabinoid system”.

These discoveries were followed by the development of a number of CB1- and CB2-selective antagonists that in some CB1 or CB2 receptor-containing systems also produce “inverse cannabimimetic effects“, effects opposite in direction from those produced by cannabinoid receptor agonists. This review focuses on the CB1-selective antagonists, SR141716A, AM251, AM281 and LY320135, and discusses possible mechanisms by which these ligands produce their inverse effects:

(1) competitive surmountable antagonism at CB1 receptors of endogenously released endocannabinoids,

(2) inverse agonism resulting from negative, possibly allosteric, modulation of the constitutive activity of CB1 receptors in which CB1 receptors are shifted from a constitutively active “on” state to one or more constitutively inactive “off” states and

(3) CB1 receptor-independent mechanisms, for example antagonism of endogenously released adenosine at A1 receptors. Recently developed neutral competitive CB1 receptor antagonists, which are expected to produce inverse effects through antagonism of endogenously released endocannabinoids but not by modulating CB1 receptor constitutive activity, are also discussed. So too are possible clinical consequences of the production of inverse cannabimimetic effects, there being

convincing evidence that released endocannabinoids can have “autoprotective” roles.

So these drugs would function sort of like the serotonin reuptake inhibitors, so that there would be more endocannabinoids available in the system to do their autoprotective jobs?

+++++=

Pertwee 2006

Int J Obes (Lond). 2006 Apr;30 Suppl 1:S13-8.

Links

The pharmacology of cannabinoid receptors and their ligands: an overview.

Pertwee RG.

School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, UK. rgp@abdn.ac.uk

Mammalian tissues express at least two cannabinoid receptor types, CB1 and CB2, both G protein coupled.

….CB1 receptors are found predominantly at nerve terminals where they mediate inhibition of transmitter release.

….CB2 receptors occur mainly on immune cells,

…….one of their roles being to modulate cytokine release.

Endogenous agonists

….for cannabinoid receptors also exist,

…..and are all eicosanoids.

The first-discovered of these ‘endocannabinoids’ was

……….arachidonoylethanolamide and there is convincing evidence

…..that this ligand and some of its metabolites can activate vanilloid VRI (TRPV1) receptors.

Certain cannabinoids also appear to have TRPV1-like and/or non-CB1, non-CB2, non-TRPV1 targets.

Several CB1- and CB2-selective agonists and antagonists have been developed.

………Antagonists include the CB1-selective SR141716A, AM251, AM281 and LY320135, and ………..the CB2-selective SR144528 and AM630.

These all behave as inverse agonists, one indication that CB1 and CB2 receptors can exist in a constitutively active state.

‘Neutral’ cannabinoid receptor antagonists have also been developed.

………CB1 and/or CB2 receptor activation appears to

…….ameliorate inflammatory and

……..neuropathic pain and certain multiple sclerosis symptoms.

This might be exploited clinically by using CB1, CB2 or CB1/CB2 agonists,

……..or inhibitors of the membrane transport or catabolism of endocannabinoids

……..that are released in increased amounts, at least in animal models of pain and multiple sclerosis.

We have recently discovered the presence of an allosteric site on the CB1 receptor. ………..Consequently, it may also prove possible to enhance

‘autoprotective’ effects of released endocannabinoids

….with CB1 allosteric enhancers or, indeed,

…….to reduce proposed ‘autoimpairing’ effects of released endocannabinoids such as excessive food intake with CB1 allosteric antagonists.  obesity

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Woelkart, Salo-Ahen & Bauer 2008

Curr Top Med Chem. 2008;8(3):173-86.

Links

CB receptor ligands from plants.

Woelkart K, Salo-Ahen OM, Bauer R.

Institute of Pharmaceutical Sciences, Department of Pharmacognosy, Karl-Franzens-University Graz, 8010 Graz, Austria.

Advances in understanding the physiology and pharmacology of the endogenous cannabinoid system have potentiated the interest of cannabinoid receptors as potential therapeutic targets. Cannabinoids have been shown to modulate a variety of immune cell functions and have therapeutic implications on central nervous system (CNS) inflammation, chronic inflammatory conditions such as arthritis, and may be therapeutically useful in treating autoimmune conditions such as multiple sclerosis.

Many of these drug effects occur through cannabinoid receptor signaling mechanisms and the modulation of cytokines and other gene products. Further, endocannabinoids have been found to have many physiological and patho-physiological functions, including mood alteration and analgesia, control of energy balance, gut motility, motor and co-ordination activities, as well as alleviation of neurological, psychiatric and eating disorders.

Plants offer a wide range of chemical diversity and have been a growing domain in the search for effective cannabinoid ligands. Cannabis sativa L. with the known plant cannabinoid, Delta(9-)tetrahydrocannabinol (THC) and Echinacea species with the cannabinoid (CB) receptor-binding lipophilic alkamides are the best known herbal cannabimimetics. This review focuses on the state of the art in CB ligands from plants, as well their possible therapeutic and immunomodulatory effects.

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This is in the food section:

Viveros et al 2008

Endocr Metab Immune Disord Drug Targets. 2008 Sep;8(3):220-30.

Links

Critical role of the endocannabinoid system in the regulation of food intake and energy metabolism, with phylogenetic, developmental, and pathophysiological implications.

Viveros MP, de Fonseca FR, Bermudez-Silva FJ, McPartland JM.

Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid, 28040 Madrid, Spain. pazviver@bio.ucm.es

energy homeostasis

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Anisman et al 1996

CMAJ. 1996 Oct 1;155(7):867-74.

Links

Neuroimmune mechanisms in health and disease: 1. Health.

Anisman H, Baines MG, Berczi I, Bernstein CN, Blennerhassett MG, Gorczynski RM, Greenberg AH, Kisil FT, Mathison RD, Nagy E, Nance DM, Perdue MH, Pomerantz DK, Sabbadini ER, Stanisz A, Warrington RJ.

Department of Psychology, Carleton University, Ottawa, Ont.

A novel scientific discipline that examines the complex interdependence of the neural, endocrine and immune systems in health and disease has emerged in recent years. In health, the

neuroimmunoregulatory network

is fundamental to host defense and to the

transfer of immunity to offspring;

Linda note:  That is ultimately why this information is being accumulated in a section on attachment.  I believe that what secure attachment provides – and as the article in child maltreatment points out, this is not about a perfectly secure environment – this is about secure attachment which IS what is transferred to offspring as the best protective factor, the best immunity on all levels, that is possible for them to have as they go through their lives.  Secure attachment IS the foundation of the immune system, I believe – still….

the network also plays important roles in intestinal physiology and in tissue regeneration, healing and reproduction.

The proliferation of lymphocytes in

………primary lymphoid organs (bone marrow, bursa of Fabricius [in birds] and thymus) and in

………secondary lymphoid organs (spleen, lymph nodes and mucosal lymphoid tissue)

depends on prolactin [single-chain protein hormone closely related to growth hormone  – increases the secretion of progesterone by the ovary  – released from the pituitary gland that prompts milk production (lactation)] and growth hormone.

………..These hormones allow immune cells to respond to antigen and to soluble mediators, called cytokines.

Immune-derived cytokines are capable of inducing fever

………..and of altering neuro-transmitter activity in the brain

………and hormone secretion by the pituitary gland.

The activation of the hypothalamus-pituitary-adrenal axis by cytokines leads to immunosuppression.

[epinephrine and somatostatin]

anti-inflammatory

Lymphoid organs are innervated, and tissue mast cells respond to neurologic stimuli. In general,

….acetylcholine and substance P exert immunostimulatory and proinflammatory effects,

…..whereas

epinephrine and somatostatin are

immunosuppressive and anti-inflammatory.

…………..In this article, the authors predict that novel approaches to immunomodulation will be possible by altering the level or efficacy of immunoregulatory hormones and neurotransmitters.

See also:

CMAJ. 1996 Oct 15;155(8):1075-82.

Links

Neuroimmune mechanisms in health and disease: 2. Disease.

Anisman H, Baines MG, Berczi I, Bernstein CN, Blennerhassett MG, Gorczynski RM, Greenberg AH, Kisil FT, Mathison RD, Nagy E, Nance DM, Perdue MH, Pomerantz DK, Sabbadini ER, Stanisz A, Warrington RJ.

Department of Psychology, Carloton University, Ottawa, Ont.

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Markovic 2004

Srp Arh Celok Lek. 2004 May-Jun;132(5-6):187-93.

Links

[Interaction involving the thymus and the hypothalamus-pituitary axis, immunomodulation by hormones]

[Article in Serbian]

Marković L.

Perfectly projected and impeccably created, the endocrine system precisely regulates the most delicate immune processes.

The immune and neuroendocrine systems are

….two essential physiological components of mammalian organisms

important for protection from the infection and disease on one hand,

and on the other, for regulation of metabolism and other physiological activities;

… evidence has been found indicating that there is active and dynamic collaboration of these systems in the execution of their designated functions.

These interactions occur at many stages of embryonic and neonatal development, and they are a continual part of normal homeostatic balance necessary to preserve health.

……There is communication between neuroendocrine and immune system via cytokines, neurotransmitters and peptide hormones which act, in both systems, through the same receptor molecules

Many investigators have reported the increased thymic weight in experimental animals due to both castration and adrenalectomy. The discovery from 1898 revealing that thymus was enlarged in castrated rabbits has been considered the embryo of hybrid medical discipline, i.e. the immunoendocrinology. In the actual literature, at least in that available to us, it has not been noted that the appearance of the eunuchs, i.e. the castrates, stimulated the analytical approach to this phenomenon.

Endocrine influences appear to be a part of bidirectional circuitry, namely,

thymic hormones also regulate the release of hormones from the pituitary gland.

Physiologically, thymus is under neuroendocrine control. It is apparent that the circulating levels of distinct peptide hormones are necessary to maintain a series of biological functions related both to microenvironmental and lymphoid cells of the organ. The neuroendocrine control of the thymus appears to be extremely complex, with apparent presence of complete

………… intrathymic biological circuitry involving the production of pituitary hormones,

………..as well as the expression of their respective receptors by thymic cell.

The influence of gonadectomy on the humoral immunity has been controversial. All investigations agree that women have higher titres of all classes of circulating antibodies than men. The application of estrogens stimulated the formation of antibodies in the circulation. Then, if there were no sex glands, the immune response of the individual would be enhanced. Both the cellular and the humoral immune response is more powerful in the adult normal women than in men of the same age. The immune response is different in different sexes meaning that there is a sexual dimorphism. Again, see Hawks and Doves for intra-gender differences as well

This difference has not been noted before the puberty. It has been noticed that the substitution therapy has alleviated the late skin hypersensitivity. The estrogens have also curtailed the rejection time of the transplant and all reactions in which T-effector lymphocytes have been involved. NK-cells and T-lymphocytes activities have been decreased by the action of estrogens, as well as the release of thymus hormones. Cortical RE cells express a surface antigen, gp200-MR6, which plays a significant role in thymocyte differentiation. Irrespectively of which pathway may be triggered by neuroendocrine factors, the effects are pleiotropic and result in modulation of the expression of several genes in different cell types. Thymic neuroendocrine polypeptides are the source of self-antigens presented by MHC molecules enabling the differentiation of haematopoietic stem cells.

Thymic nurse cells also produce thymosins beta 3 and beta 4 and display a neuroendocrine cell specific immunophenotype (IP): Thy-1+, A2B5+, TT+, TE4+, UJ13/A+, UJ127.11+, UJ167.11+, UJ181.4+ and presence of common leukocyte antigen (CLA+). GH enhances thymocyte release from TNCs, as well as the reconstitution of these lymphoepithelial complexes. Similar to its role as a regulator of bone metabolism through regulating osteoprotegerin (OPG) production, the estrogen is involved in the processes of thymocyte development although aromatase mRNA has not been detectable in the thymus. While the increase of TNC number during lactation may be linked to the process of reconstruction of the thymic lymphoid population, the increased activity of lymphoepithelial interactions on GD14 may be associated with thymic engagement in pregnancy-induced immune processes.

The major antigens in the experimental autoimmune hypophysitis in rats are growth hormone, thyrotropin, and luteinizing hormone. The intrathymic T-lymphocyte selection is a complex, multistep process, influenced by several functionally specialized RE cells and under immuno-neuroendocrine regulation control reflecting the dynamic changes of the mammalian organism. In HIV-1-infected adults treated with growth hormone, thymic mass and circulating naive CD4 T cells are increased.

The treatment would be easier for the diseased, as well as to us, the physicians, if we were aware of two millennia old wisdom–that the disease is a visit of God.

++++

Karsak et al 2007

Science. 2007 Jun 8;316(5830):1494-7.

Links

Attenuation of allergic contact dermatitis through the endocannabinoid system.

Karsak M, Gaffal E, Date R, Wang-Eckhardt L, Rehnelt J, Petrosino S, Starowicz K, Steuder R, Schlicker E, Cravatt B, Mechoulam R, Buettner R, Werner S, Di Marzo V, Tüting T, Zimmer A.

Department of Molecular Psychiatry, University of Bonn, Germany.

Allergic contact dermatitis affects about 5% of men and 11% of women in industrialized countries and is one of the leading causes for occupational diseases.

….In an animal model for cutaneous [relating to or existing on or affecting the skin] contact hypersensitivity, we show that mice lacking both known cannabinoid receptors display exacerbated allergic inflammation.

In contrast, fatty acid amide hydrolase-deficient mice, which have increased levels of the endocannabinoid anandamide, displayed reduced allergic responses in the skin.

Cannabinoid receptor antagonists exacerbated allergic inflammation,

….whereas receptor agonists attenuated inflammation.

……..These results demonstrate a

protective role of the endocannabinoid system in contact allergy in the skin

and suggest a target for therapeutic intervention.

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Zheng et al 2008

Cancer Res. 2008 May 15;68(10):3992-8.

Links

The cannabinoid receptors are required for ultraviolet-induced inflammation and skin cancer development.

Zheng D, Bode AM, Zhao Q, Cho YY, Zhu F, Ma WY, Dong Z.

Hormel Institute, University of Minnesota, Austin, Minnesota, USA. zgdong@hi.umn.edu

Solar UV irradiation is an important carcinogen that leads to the development of skin cancer, which is the most common human cancer.

However, the receptors that mediate UV-induced skin carcinogenesis have not yet been unequivocally identified.

Here we showed that UV irradiation directly activates cannabinoid receptors 1 and 2 (CB1/2).

Notably, our data indicated that the absence of the CB1/2 receptors in mice results in a dramatic resistance to UVB-induced inflammation and a marked decrease in UVB-induced skin carcinogenesis. A marked attenuation of UVB-induced activation of mitogen-activated protein kinases and nuclear factor- kappaB was associated with CB1/2 deficiency. These data provide direct evidence indicating that the

CB1/2 receptors play a key role in UV-induced inflammation and skin cancer development.

++++++++

IIMPORTANT – LINK BETWEEN SKIN CANCER AND OBESITY

+++

Katiyar & Meeran 2007

Free Radic Biol Med. 2007 Jan 15;42(2):299-310. Epub 2006 Oct 28.

Links

Obesity increases the risk of UV radiation-induced oxidative stress and activation of MAPK and NF-kappaB signaling.

Katiyar SK, Meeran SM.

Department of Dermatology, University of Alabama at Birmingham, P.O. Box 202, Volker Hall 557, 1670 University Boulevard, Birmingham, AL 35294, USA. skatiyar@uab.edu

Obesity has been implicated in several diseases, including cancer; however, the relationship of obesity and susceptibility to ultraviolet (UV) radiation-caused skin diseases has not been investigated.

As UV-induced oxidative stress has been implicated in several skin diseases, we assessed the role of obesity on UVB-induced oxidative stress in genetically obese Lep(ob)/Lep(ob) (leptin-deficient) mice. Here, we report that chronic exposure to UVB (120 mJ/cm(2)) resulted in greater oxidative stress in the skin of obese mice in terms of higher levels of H(2)O(2) and NO production, photo-oxidative damage of lipids and proteins, and greater depletion of antioxidant defense enzymes, like glutathione, glutathione peroxidase, and catalase. As UV-induced oxidative stress mediates activation of MAPK and NF-kappaB signaling pathways, we determined the effects of UVB on these pathways in obese mice. Exposure of obese mice to UVB resulted in phosphorylation of ERK1/2, JNK, and p38 proteins of the MAPK family. Compared to wild-type mice, the obese mice exhibited higher levels of phosphorylation of these proteins, greater activation of NF-kappaB/p65, and higher levels of circulating proinflammatory cytokines, including TNF-alpha, IL-1beta and IL-6, on UVB irradiation.

Taking these results together, our study suggests for the first time that obesity in mice is associated with greater susceptibility to UVB-induced oxidative stress and therefore may be a risk factor for skin diseases associated with UVB-induced oxidative stress.

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Invest Ophthalmol Vis Sci. 2008 Oct;49(10):4535-44. Epub 2008 Jun 19.

Links

Cannabinoid receptors in conjunctival epithelium: identification and functional properties.

Iribarne M, Torbidoni V, Julián K, Prestifilippo JP, Sinha D, Rettori V, Berra A, Suburo AM.

Facultad de Ciencias Biomédicas, Universidad Austral, Pilar, Buenos Aires, Argentina.

PURPOSE: Preservation of the ocular surface barrier requires complex control of epithelial [membranous tissue covering internal organs and other internal surfaces of the body] cell proliferation and inflammation mechanisms. The endocannabinoid system may be regulating these processes. Therefore, the authors explored the presence and properties of cannabinoid receptors (CB1 and CB2) in conjunctival epithelial cells. METHODS: ….

Functional responses, such as decreased cAMP levels, proliferation, and modulation of stress signaling pathways, were mediated by CB1 and CB2 stimulation. Thus, these receptors might be involved in the regulation of epithelial renewal and inflammatory processes at the ocular surface.

PMID: 18566465 [PubMed – indexed for MEDLINE

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http://www.nsf.gov/news/news_summ.jsp?cntn_id=109601

National Science Foundation

Press Release 07-059
“Nurse Cells” Make Life and Death Decisions for Infection-Fighting Cells

May 29, 2007

“Nurse cells” play an important role in deciding which developing infection-fighting cells, called T cells, live and which die, according to research funded by the National Science Foundation (NSF) and reported in the June issue of the journal Experimental Biology and Medicine.

The infection-fighting cells, known as thymocytes or T cells, live in the thymus, an organ in the upper portion of the chest. Loss of the thymus results in severe immunodeficiency and increased susceptibility to infection. The function of T cells produced by the thymus is to recognize harmful invaders. Once invaders have been identified, T cells then attempt to eliminate disease-infected cells.

“In early studies, it was suggested that thymic nurse cells only removed non-functional thymocytes,” said Eve Barak, program director in NSF’s Division of Molecular and Cellular Biology. “This research shows that nurse cells are performing a much bigger role in the thymus than we thought.”

Thymic nurse cells were given their name because of their close relationship with thymocytes. These nurse cells have been reported to take up as many as 50 destined-to-die thymocytes into their own cell bodies.

Thymic nurse cells were discovered in 1980. Their existence was debated because many scientists found it difficult to believe that a cell could internalize another cell, said Jerry Guyden, a biologist at the City College of New York and lead researcher.

The thymus is present in most vertebrates, with a similar structure and function as the human thymus. Animal thymic tissue sold in butcher shops or at meat counters is known as sweetbread.

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van der Stelt & Di Marzo 2005

Neuromolecular Med. 2005;7(1-2):37-50.

Links

Cannabinoid receptors and their role in neuroprotection.

van der Stelt M, Di Marzo V.

Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078, Pozzuoli, NA, Italy.

Two G protein-coupled receptors

…..for marijuana’s psychoactive component, Delta9-tetrahydrocannabinol, ……have been cloned to date, …….the cannabinoid CB1 and CB2 receptors.

These two proteins, the endogenous lipids that activate them, also known as endocannabinoids, and the proteins for the biosynthesis and inactivation of these ligands constitute the endocannabinoid system.

Evidence has accumulated over the last few years suggesting that endocannabinoid-based drugs may potentially be useful to reduce the effects of neurodegeneration. In fact, exogenous and endogenous cannabinoids were shown to exert neuroprotection in a variety of in vitro and in vivo models of neuronal injury via different mechanisms,

such as prevention

of excitotoxicity by cannabinoid CB1-mediated inhibition of glutamatergic transmission,

reduction of

…calcium influx,

….anti-oxidant activity,

…activation of the phosphatidylinositol 3-kinase/protein kinase B pathway, ….induction of phosphorylation of extracellular regulated kinases

….and the expression of transcription factors and neurotrophins,

….. lowering of cerebrovasoconstriction and induction of hypothermia.

The release of endocannabinoids during neuronal injury may constitute a protective response. If this neuroprotective function of cannabinoid receptor activation can be transferred to the clinic, it might represent an interesting target to develop neuroprotective agents.

See also:

The role of the CB1 cannabinoid receptor and its endogenous ligands, anandamide and 2-arachidonoylglycerol, in amphetamine-induced behavioural sensitization.

Thiemann G, van der Stelt M, Petrosino S, Molleman A, Di Marzo V, Hasenöhrl RU.

Behav Brain Res. 2008 Mar 5;187(2):289-96. Epub 2007 Sep 25.

PMID: 17988751 [PubMed – indexed for MEDLINE]

Related Articles

A role for endocannabinoids in the generation of parkinsonism and levodopa-induced dyskinesia in MPTP-lesioned non-human primate models of Parkinson’s disease.

van der Stelt M, Fox SH, Hill M, Crossman AR, Petrosino S, Di Marzo V, Brotchie JM.

FASEB J. 2005 Jul;19(9):1140-2. Epub 2005 May 13.

PMID: 15894565 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

9:

The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders.

van der Stelt M, Di Marzo V.

Eur J Pharmacol. 2003 Nov 7;480(1-3):133-50. Review.

PMID: 14623357 [PubMed – indexed for MEDLINE]

Related Articles

10:

CB1 cannabinoid receptors and on-demand defense against excitotoxicity.

Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutiérrez SO, van der Stelt M, López-Rodriguez ML, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C, Lutz B.

Science. 2003 Oct 3;302(5642):84-8.

PMID: 14526074 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

11:

Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: role of vanilloid receptors and lipoxygenases.

Veldhuis WB, van der Stelt M, Wadman MW, van Zadelhoff G, Maccarrone M, Fezza F, Veldink GA, Vliegenthart JF, Bär PR, Nicolay K, Di Marzo V.

J Neurosci. 2003 May 15;23(10):4127-33.

PMID: 12764100 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

12:

Acute neuronal injury, excitotoxicity, and the endocannabinoid system.

van der Stelt M, Veldhuis WB, Maccarrone M, Bär PR, Nicolay K, Veldink GA, Di Marzo V, Vliegenthart JF.

Mol Neurobiol. 2002 Oct-Dec;26(2-3):317-46. Review.

PMID: 12428763 [PubMed – indexed for MEDLINE]

Related Articles

13:

Exogenous anandamide protects rat brain against acute neuronal injury in vivo.

van der Stelt M, Veldhuis WB, van Haaften GW, Fezza F, Bisogno T, Bar PR, Veldink GA, Vliegenthart JF, Di Marzo V, Nicolay K.

J Neurosci. 2001 Nov 15;21(22):8765-71.

PMID: 11698588 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

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Maccarrone & Finazzi-Agro 2003

Cell Death Differ. 2003 Sep;10(9):946-55.

Links

The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis.

Maccarrone M, Finazzi-Agró A.

Department of Biomedical Sciences, University of Teramo, Teramo, Italy. Maccarrone@vet.unite.it

Endocannabinoids are a

…new class of lipid mediators,

….which include amides, esters and ethers of long-chain polyunsaturated fatty acids.

Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the main endogenous agonists of cannabinoid receptors

….able to mimic several pharmacological effects of Delta-9-tetrahydrocannabinol,

…..the active principle of Cannabis sativa preparations like hashish and marijuana.

The pathways leading to the synthesis and release of AEA and 2-AG from neuronal and non-neuronal cells are still rather uncertain.

….. Instead, it is known that the activity of AEA is limited by cellular uptake through a specific membrane transporter,

…. followed by intracellular degradation by a fatty acid amide hydrolase.

Together with AEA and congeners these proteins form the ‘endocannabinoid system’.

Here, the involvement of AEA in apoptosis and the underlying signal transduction pathways

…..will be reviewed, along with the metabolic routes and the molecular targets of this endocannabinoid. Also, recent findings on the apoptotic potential of AEA for neuronal cell differentiation and brain development will be discussed.

See also:

Expression of the endocannabinoid system in the bi-potential HEL cell line: commitment to the megakaryoblastic lineage by 2-arachidonoylglycerol.

Catani MV, Fezza F, Baldassarri S, Gasperi V, Bertoni A, Pasquariello N, Finazzi-Agrò A, Sinigaglia F, Avigliano L, Maccarrone M.

J Mol Med. 2009 Jan;87(1):65-74. Epub 2008 Sep 27.

PMID: 18820887 [PubMed – in process]

Related Articles

The endocannabinoid system in neurodegeneration.

Battista N, Fezza F, Finazzi-Agrò A, Maccarrone M.

Ital J Biochem. 2006 Sep-Dec;55(3-4):283-9. Review.

PMID: 17274532 [PubMed – indexed for MEDLINE]

Related Articles

Effect of lipid rafts on Cb2 receptor signaling and 2-arachidonoyl-glycerol metabolism in human immune cells.

Bari M, Spagnuolo P, Fezza F, Oddi S, Pasquariello N, Finazzi-Agrò A, Maccarrone M.

J Immunol. 2006 Oct 15;177(8):4971-80.

PMID: 17015679 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

Biochemical changes in endocannabinoid system are expressed in platelets of female but not male migraineurs.

Cupini LM, Bari M, Battista N, Argirò G, Finazzi-Agrò A, Calabresi P, Maccarrone M.

Cephalalgia. 2006 Mar;26(3):277-81.

PMID: 16472333 [PubMed – indexed for MEDLINE]

Related Articles

Lipid rafts control signaling of type-1 cannabinoid receptors in neuronal cells. Implications for anandamide-induced apoptosis.

Bari M, Battista N, Fezza F, Finazzi-Agrò A, Maccarrone M.

J Biol Chem. 2005 Apr 1;280(13):12212-20. Epub 2005 Jan 18.

PMID: 15657045 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

A critical interaction between dopamine D2 receptors and endocannabinoids mediates the effects of cocaine on striatal gabaergic Transmission.

Centonze D, Battista N, Rossi S, Mercuri NB, Finazzi-Agrò A, Bernardi G, Calabresi P, Maccarrone M.

Neuropsychopharmacology. 2004 Aug;29(8):1488-97.

PMID: 15100701 [PubMed – indexed for MEDLINE]

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Pharmacol Biochem Behav. 2005 Jun;81(2):239-47.

Links

Functional neuroanatomy of the endocannabinoidsystem.

Pazos MR, Núñez E, Benito C, Tolón RM, Romero J.

Laboratorio de Apoyo a la Investigación, Fundación Hospital Alcorcón, C/ Budapest 1, Alcorcón, Madrid 28922, Spain.

Several components of the endocannabinoid system have been fully characterized. Among them are two types of cannabinoid receptors (termed CB1 and CB2), endogenous ligands for those receptors (referred to as “endocannabinoids”), and specific enzymes responsible for their degradation and inactivation. The study of the distribution and abundance of these elements in the central nervous system has provided the basis for the well-known effects of exogenous (both natural and synthetic) and endogenous cannabinoids. In addition, recent developments also support the idea that the endocannabinoid system plays a critical neuromodulatory role in the central nervous system. For instance, cannabinoid CB1 receptor activation is known to modify the release of several neurotransmitters, such as glutamate and gamma-aminobutyric acid. However, we still lack knowledge on fundamental aspects of the physiological roles of this system. Interestingly, changes in the distribution and activity of some of these components of the endocannabinoid system have been reported under different pathological conditions, suggesting their possible involvement in the pathogenesis of these diseases. As comprehensive excellent reviews have been recently published, the present review will focus only on the most recent advances in the field, considering a new perspective of the endocannabinoid system as composed of both neuronal and glial divisions.

PMID: 15936805 [PubMed – indexed for MEDLINE

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Karanian et al 2005

J Neurosci. 2005 Aug 24;25(34):7813-20.

Links

Dual modulation of endocannabinoid transport and fatty acid amide hydrolase protects against excitotoxicity.

Karanian DA, Brown QB, Makriyannis A, Kosten TA, Bahr BA.

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA.

The endocannabinoid system has been suggested

to elicit signals

that defend against several disease states

including excitotoxic brain damage.

Besides direct activation with CB1 receptor agonists,

…..cannabinergic signaling can be modulated

….. through inhibition of endocannabinoid transport

…..and fatty acid amide hydrolase (FAAH),

…..two mechanisms of endocannabinoid inactivation.

… results indicate that dual modulation of the endocannabinoid system with AM374/AM404

elicits neuroprotection through the CB1 receptor.

…..The transporter and FAAH are modulatory sites that may be exploited to enhance cannabinergic signaling for therapeutic purposes.

See also:

Neurobiol Dis. 2005 Nov;20(2):207-17.

Links

Decreased endocannabinoid levels in the brain and beneficial effects of agents activating cannabinoid and/or vanilloid receptors in a rat model of multiple sclerosis.

Cabranes A, Venderova K, de Lago E, Fezza F, Sánchez A, Mestre L, Valenti M, García-Merino A, Ramos JA, Di Marzo V, Fernández-Ruiz J.

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.

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Wise et al 2007

Eur J Pharmacol. 2007 Feb 14;557(1):44-8. Epub 2006 Nov 10.

Links

Assessment of anandamide’s pharmacological effects in mice deficient of both fatty acid amide hydrolase and cannabinoid CB1 receptors.

Wise LE, Shelton CC, Cravatt BF, Martin BR, Lichtman AH.

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, United States.

In the present study, we investigated whether anandamide produces its behavioral effects through a cannabinoid CB(1) receptor mechanism of action. The behavioral effects of anandamide were evaluated in mice that lacked both fatty acid amide hydrolase (FAAH) and cannabinoid CB(1) receptors (DKO) as compared to FAAH (-/-), cannabinoid CB(1) (-/-), and wild type mice. Anandamide produced analgesia, catalepsy, and hypothermia in FAAH (-/-) mice, but failed to elicit any of these effects in the other three genotypes. In contrast, anandamide decreased locomotor behavior regardless of genotype, suggesting the involvement of multiple mechanisms of action, including its products of degradation. These findings indicate that the cannabinoid CB(1) receptor is the predominant target mediating anandamide’s behavioral effects.

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Labar & Michaux 2007

Chem Biodivers. 2007 Aug;4(8):1882-902.

Links

Fatty acid amide hydrolase: from characterization to therapeutics.

Labar G, Michaux C.

Unité de Chimie pharmaceutique et de Radiopharmacie, Ecole de Pharmacie, Faculté de Médecine, Université catholique de Louvain, Avenue E. Mounier 73.40, B-1200 Bruxelles.

Fatty acid amide hydrolase (FAAH) is an

…integral membrane enzyme within the amidase-signature family

….that terminates the action of several endogenous lipid messengers,

…. including oleamide and the endocannabinoid anandamide.

The hydrolysis of such messengers

…. leads to molecules devoid of biological activity, and, therefore,

….modulates a number of neurobehavioral processes in mammals, including

….pain,

….sleep,

….feeding, and

…. locomotor activity.

Investigations into the structure and function of FAAH, its biological and therapeutic implications, as well as a description of different families of FAAH inhibitors are the topic of this review.

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Ortega-Gutierrez et al 2004

Biochemistry. 2004 Jun 29;43(25):8184-90.

Links

Comparison of anandamide transport in FAAH wild-type and knockout neurons: evidence for contributions by both FAAH and the CB1 receptor to anandamide uptake.

Ortega-Gutiérrez S, Hawkins EG, Viso A, López-Rodríguez ML, Cravatt BF.

The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

The cellular inactivation

…..of the endogenous cannabinoid (endocannabinoid) anandamide (AEA)

……represents a controversial and intensely investigated subject.

This process has been proposed to involve two proteins,

….a transporter that promotes the cellular uptake of AEA

….and fatty acid amide hydrolase (FAAH),

……..which hydrolyzes AEA to arachidonic acid.

However, whereas the role of FAAH in AEA metabolism is well-characterized,

the identity of the putative AEA transporter remains enigmatic.

Indeed, the indirect pharmacological evidence used to support the existence of an AEA transporter has been suggested also to be compatible

……with a model in which AEA uptake is driven by simple diffusion coupled to FAAH metabolism.

Here, we have directly addressed the contribution of FAAH to AEA uptake by examining this process in neuronal preparations from FAAH(-/-) mice and in the presence of the uptake inhibitor UCM707. The results of these studies reveal that

(i) care should be taken to avoid the presence of artifacts when studying the cellular uptake of lipophilic molecules like AEA,

(ii) FAAH significantly contributes to AEA uptake,

……..especially with longer incubation times, and

(iii) a UCM707-sensitive protein(s) distinct from FAAH also participates in AEA uptake.

Interestingly, the FAAH-independent component of AEA transport was significantly reduced by pretreatment of neurons with the cannabinoid receptor 1 (CB1) antagonist SR141716A. ………Collectively, these results indicate that the protein-dependent uptake of AEA

……is largely mediated by

…… known constituents of the

endocannabinoid system (FAAH and the CB1 receptor),

….although a partial contribution of an additional UCM707-sensitive protein is also suggested.

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NEUROVASCULAR ACTIVITIES

Maccarrone et al 2006

From abstract – Italy

Article title:  Regulation by cannabinoid receptors of anandamide transport across the blood-brain barrier and through other endothelial cells.

The endocannabinoid anandamide (AEA)

……has many neurovascular activities.

However, it is not yet clear how AEA can be metabolized at the neurovascular interface, and how it can move through the vascular and the cerebral compartments. The results reported in this article show that isolated bovine brain microvessels, an ex vivo

model of the blood-brain barrier, have detectable levels of endogenous AEA and possess the biochemical machinery to bind and metabolize it, i.e. type-1 and type-2 cannabinoid receptors (CB1R and CB2R), a selective AEA membrane transporter (AMT), an AEA-degrading fatty acid amide hydrolase, and the AEA-synthesizing enzymes N-acyltransferase and N-acyl-phosphatidylethanolamines-specific phospholipase D.

We also show that activation of CB1R enhances AMT activity through increased nitric oxide synthase (NOS) activity and subsequent increase of NO production. AMT activity is instead reduced by activation of CB2R, which inhibits NOS and NO release. In addition, binding experiments and immunoelectronmicroscopy demonstrate that different endothelial cells vary in the expression of CB1R and CB2R on the luminal and/or abluminal sides. The different localization of CBRs can lead to a diverse effect on AMT activity on the luminal and abluminal membranes, suggesting that

the distribution of these receptors may drive AEA directional transport

through the blood-brain barrier and other endothelial cells.

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See also:

The endocannabinoid system in neurodegeneration.

Battista N, Fezza F, Finazzi-Agrò A, Maccarrone M.

Ital J Biochem. 2006 Sep-Dec;55(3-4):283-9. Review.

PMID: 17274532 [PubMed – indexed for MEDLINE]

Related Articles

Jekyll and hyde: two faces of cannabinoid signaling in male and female fertility.

Wang H, Dey SK, Maccarrone M.

Endocr Rev. 2006 Aug;27(5):427-48. Epub 2006 May 8. Review.

PMID: 16682502 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

Effect of lipid rafts on Cb2 receptor signaling and 2-arachidonoyl-glycerol metabolism in human immune cells.

Bari M, Spagnuolo P, Fezza F, Oddi S, Pasquariello N, Finazzi-Agrò A, Maccarrone M.

J Immunol. 2006 Oct 15;177(8):4971-80.

PMID: 17015679 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

Human adipose tissue binds and metabolizes the endocannabinoids anandamide and 2-arachidonoylglycerol.

Spoto B, Fezza F, Parlongo G, Battista N, Sgro’ E, Gasperi V, Zoccali C, Maccarrone M.

Biochimie. 2006 Dec;88(12):1889-97. Epub 2006 Aug 22.

PMID: 16949718 [PubMed – indexed for MEDLINE]

Related Articles

New insights into endocannabinoid degradation and its therapeutic potential.

Bari M, Battista N, Fezza F, Gasperi V, Maccarrone M.

Mini Rev Med Chem. 2006 Mar;6(3):257-68. Review.

PMID: 16515464 [PubMed – indexed for MEDLINE]

Related Articles

Biochemical changes in endocannabinoid system are expressed in platelets of female but not male migraineurs.

Cupini LM, Bari M, Battista N, Argirò G, Finazzi-Agrò A, Calabresi P, Maccarrone M.

Cephalalgia. 2006 Mar;26(3):277-81.

PMID: 16472333 [PubMed – indexed for MEDLINE]

Related Articles

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CANCER FIGHTING

Michalski et al 2008

From abstract – Department of General Surgery, Technische Universität Munich, Munich, Germany. christoph.michalski@gmx.de

Cannabinoids exert antiproliferative properties in a variety of malignant tumors, including pancreatic ductal adenocarcinoma (PDAC).

In our study, we quantitatively evaluated the immunoreactivity for cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptors as well as for the endocannabinoid metabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MGLL).

Furthermore, quantitative real-time RT-PCR for CB1, CB2, FAAH and MGLL in normal pancreas and pancreatic cancer tissues was performed.

…… Immunoreactivity scores and QRT-PCR expression levels were correlated with the clinico-pathological (TNM, survival, pain) status of the patients.

……… Evaluation of endocannabinoid levels revealed that these remained unchanged in PDAC compared to the normal pancreas.

Patients with high CB1 receptor levels in enlarged nerves in PDAC had a lower combined pain score (intensity, frequency, duration; p = 0.012).

There was a significant relationship between

…..low CB1 receptor immunoreactivity or mRNA expression levels … or high FAAH and MGLL cancer cell immunoreactivity … and longer survival of PDAC patients.

These results are underlined by a significant correlation of high pain scores and increased survival …..

….CB2 receptor immunoreactivity, CB2 receptor, FAAH and MGLL mRNA expression levels did not correlate with survival.

Therefore, changes in the levels of endocannabinoid metabolizing enzymes and cannabinoid receptors on pancreatic cancer cells may affect prognosis and pain status of PDAC patients.

See also:

Cannabinoids reduce markers of inflammation and fibrosis in pancreatic stellate cells.

Michalski CW, Maier M, Erkan M, Sauliunaite D, Bergmann F, Pacher P, Batkai S, Giese NA, Giese T, Friess H, Kleeff J.

PLoS One. 2008 Feb 27;3(2):e1701.

PMID: 18301776 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Cannabinoids in pancreatic cancer: correlation with survival and pain.

Michalski CW, Oti FE, Erkan M, Sauliunaite D, Bergmann F, Pacher P, Batkai S, Müller MW, Giese NA, Friess H, Kleeff J.

Int J Cancer. 2008 Feb 15;122(4):742-50.

PMID: 17943729 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors.

Agarwal N, Pacher P, Tegeder I, Amaya F, Constantin CE, Brenner GJ, Rubino T, Michalski CW, Marsicano G, Monory K, Mackie K, Marian C, Batkai S, Parolaro D, Fischer MJ, Reeh P, Kunos G, Kress M, Lutz B, Woolf CJ, Kuner R.

Nat Neurosci. 2007 Jul;10(7):870-9. Epub 2007 Jun 10.

PMID: 17558404 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

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Meick et al 2000

Endocrinology. 2000 Jan;141(1):118-26.

Links

Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation.

Melck D, De Petrocellis L, Orlando P, Bisogno T, Laezza C, Bifulco M, Di Marzo V.

Istituto per la Chimica di Molecole di Interesse Biologico, Consiglio Nazionale delle Ricerche, Arco Felice (NA), Italy.

Anandamide and 2-arachidonoylglycerol (2-AG), two endogenous ligands of the CB1 and CB2 cannabinoid receptor subtypes,

…….. inhibit the proliferation of PRL-responsive human breast cancer cells (HBCCs) through down-regulation of the long form of the PRL receptor (PRLr).

Here we report that

1) anandamide and 2-AG inhibit the nerve growth factor (NGF)-induced proliferation of HBCCs through suppression of the levels of NGF Trk receptors; 2) inhibition of PRLr levels results in inhibition of the proliferation of other PRL-responsive cells, the prostate cancer DU-145 cell line; and

Actions of the immune system!

3) CB1-like cannabinoid receptors are expressed in HBCCs and DU-145 cells and mediate the inhibition of cell proliferation and Trk/PRLr expression. Beta-NGF-induced HBCC proliferation was potently inhibited (IC50 = 50-600 nM) by the synthetic cannabinoid HU-210, 2-AG, anandamide, and its metabolically stable analogs, but not by the anandamide congener, palmitoylethanolamide, or the selective agonist of CB2 cannabinoid receptors, BML-190. The effect of anandamide was blocked by the CB1 receptor antagonist, SR141716A, but not by the CB2 receptor antagonist, SR144528. Anandamide and HU-210 exerted a strong inhibition of the levels of NGF Trk receptors as detected by Western immunoblotting; this effect was reversed by SR141716A. When induced by exogenous PRL, the proliferation of prostate DU-145 cells was potently inhibited (IC50 = 100-300 nM) by anandamide, 2-AG, and HU-210.

Anandamide also down-regulated the levels of PRLr in DU-145 cells. SR141716A attenuated these two effects of anandamide. HBCCs and DU-145 cells were shown to contain 1) transcripts for CB1 and, to a lesser extent, CB2 cannabinoid receptors, 2) specific binding sites for [3H]SR141716A that could be displaced by anandamide, and 3) a CB1 receptor-immunoreactive protein.

These findings suggest that endogenous cannabinoids and CB1 receptor agonists [which would be reducers, then?] are potential negative effectors of PRL- and NGF-induced biological responses,

………at least in some cancer cells.

See also:

Eur J Biochem. 1999 Aug;264(1):258-67.

Links

Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages.

Di Marzo V, Bisogno T, De Petrocellis L, Melck D, Orlando P, Wagner JA, Kunos G.

Istituto per la Chimica di Molecole di Interesse Biologico, CNR, Napoli, Italy.

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Di Marzo et al 2000

Prostaglandins Other Lipid Mediat. 2000 Apr;61(1-2):43-61.

Links

Cannabimimetic fatty acid derivatives in cancer and inflammation.

Di Marzo V, Melck D, De Petrocellis L, Bisogno T.

Istituto per la Chimica di Molecole di Interesse Biologico, Via Toiano 6, 80072, Arco Felice, Napoli, Italy. vdimarzo@icmib.na.cnr.it

Evidence for the role of the cannabimimetic fatty acid derivatives (CFADs),

… i.e. anandamide (arachidonoylethanolamide, AEA),

….2-arachidonoylglycerol (2-AG) and

….palmitoylethanolamide (PEA),  [endogenous cannabinoids]

…..in the control of inflammation and of the proliferation of tumor cells is reviewed here.

The biosynthesis of AEA, PEA, or 2-AG … in macrophages, ..for mast cells.

……….These cells also inactivate CFADs through re-uptake and/or hydrolysis and/or esterification processes. [ester n. Any of a class of organic compounds corresponding to the inorganic salts and formed from an organic acid and an alcohol]

AEA and PEA modulate cytokine and/or arachidonate

….release from macrophages in vitro,

….regulate serotonin secretion from RBL-2H3 cells,

….and are analgesic in some animal models of inflammatory pain.

However, the involvement of endogenous CFADs and cannabinoid CB(1) and CB(2) receptors in these effects is still controversial.

In human breast and prostate cancer cells, AEA and 2-AG, but not PEA, potently inhibit prolactin and/or nerve growth factor (NGF)-induced cell proliferation.

Vanillyl-derivatives of anandamide, such as olvanil and arvanil, exhibit even higher anti-proliferative activity.

These effects are due to suppression of the levels of the 100 kDa prolactin receptor or of the high affinity NGF receptors (trk), are mediated by CB(1)-like cannabinoid receptors, and are enhanced by other CFADs. Inhibition of adenylyl cyclase and activation of mitogen-activated protein kinase underlie the anti-mitogenic [mitogenic:  An agent that affects cell division] actions of AEA. The possibility that CFADs act as local inhibitors of the proliferation of human breast cancer is discussed here.

See also:

Chem Phys Lipids. 2000 Nov;108(1-2):191-209.

Links

Endocannabinoids and fatty acid amides in cancer, inflammation and related disorders.

De Petrocellis L, Melck D, Bisogno T, Di Marzo V.

Istituto di Cibernetica, Consiglio Nazionale delle Ricerche, Via Toiano 6, 80072 Arco Felice, Napoli, Italy

Brain Res Mol Brain Res. 2001 Mar 5;87(2):145-59.

Links

Evidence for an endocannabinoid system in the central nervous system of the leech Hirudo medicinalis.

Matias I, Bisogno T, Melck D, Vandenbulcke F, Verger-Bocquet M, De Petrocellis L, Sergheraert C, Breton C, Di Marzo V, Salzet M.

Laboratoire d’Endocrinologie et immunité des Annélides UPRES-A CNRS 8017, SN3-USTL, 59655 Villeneuve d’Ascq, France.

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Comelli et al 2007

Br J Pharmacol. 2007 Nov;152(5):787-94. Epub 2007 Aug 13.

Links

The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation.

Comelli F, Giagnoni G, Bettoni I, Colleoni M, Costa B.

Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milano, Italy.

: 2arachidonoylglycerol (2-AG)

is an endocannabinoid whose

hydrolysis is predominantly catalyzed

by the enzyme monoacylglycerol lipase (MAGL).

The development of MAGL inhibitors could offer an opportunity to investigate the anti-inflammatory and anti-nociceptive role of 2-AG, which have not yet been elucidated… CONCLUSIONS AND IMPLICATIONS: The present report highlighted the ability of the selective MAGL inhibitor, URB602, to prevent and treat an acute inflammatory disease without producing adverse psychoactive effects. The data presented herein also contributed to clarify the

physiological role of 2-AG in respect to inflammatory reactions, suggesting its protective role in the body.

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Jayamanne et al 2006

Br J Pharmacol. 2006 Feb;147(3):281-8.

Links

Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models.

Jayamanne A, Greenwood R, Mitchell VA, Aslan S, Piomelli D, Vaughan CW.

Pain Management Research Institute, Northern Clinical School, The University of Sydney, NSW, Australia.

While cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central CB(1) receptor-mediated motor and psychotropic side effects.

The actions of endocannabinoids,

such as anandamide

are terminated by removal from the extracellular space,

then subsequent enzymatic degradation by fatty-acid amide hydrolase (FAAH).

the FAAH inhibitor URB597

produces cannabinoid CB1 and CB2 receptor-mediated analgesia

in inflammatory pain states,

without causing the undesirable side effects

associated with cannabinoid receptor activation.

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Di Marzo et al 2001

Biochem J. 2001 Aug 15;358(Pt 1):249-55.

Links

Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells.

Di Marzo V, Melck D, Orlando P, Bisogno T, Zagoory O, Bifulco M, Vogel Z, De Petrocellis L.

Istituto per la Chimica di Molecole di Interesse Biologico, Via Toiano 6, 80072, Arco Felice, Napoli, Italy. vdimarzo@icmib.na.cnr.it

Palmitoylethanolamide (PEA) has been shown

…. to act in synergy with anandamide (arachidonoylethanolamide; AEA),

….an endogenous agonist of cannabinoid receptor type 1 (CB(1)).

This synergistic effect was reduced by the CB(2) cannabinoid receptor antagonist SR144528,

……..although PEA does not activate either CB(1) or CB(2) receptors.

Here we show that PEA potently enhances the anti-proliferative effects of AEA on human breast cancer cells (HBCCs),

…..in part by inhibiting the expression of fatty acid amide hydrolase (FAAH),

……the major enzyme catalyzing AEA degradation.

PEA stops FAAH from degrading AEA so it stays around longer – so there’s more of it

….PEA (1-10 microM) enhanced in a dose-related manner the inhibitory effect of AEA on both basal and nerve growth factor (NGF)-induced HBCC proliferation, without inducing any cytostatic effect by itself. PEA (5 microM) decreased the IC(50) values for AEA inhibitory effects by 3-6-fold. This effect was not blocked by the CB(2) receptor antagonist SR144528, and was not mimicked by a selective agonist of CB(2) receptors. PEA enhanced AEA-evoked inhibition of the expression of NGF Trk receptors,

………which underlies the anti-proliferative effect of the endocannabinoid on NGF-stimulated MCF-7 cells.

The effect of PEA was due in part to inhibition of AEA degradation, since treatment of MCF-7 cells with 5 microM

………PEA caused a approximately 30-40% down-regulation of FAAH expression and activity.

However, PEA also enhanced the cytostatic effect of the cannabinoid receptor agonist HU-210, although less potently than with AEA. …

We suggest that long-term PEA treatment of cells may positively affect the pharmacological activity of AEA, in part by inhibiting FAAH expression.

See also:

Prostaglandins Other Lipid Mediat. 2000 Apr;61(1-2):43-61.

Links

Cannabimimetic fatty acid derivatives in cancer and inflammation.

Di Marzo V, Melck D, De Petrocellis L, Bisogno T.

Istituto per la Chimica di Molecole di Interesse Biologico, Via Toiano 6, 80072, Arco Felice, Napoli, Italy. vdimarzo@icmib.na.cnr.it

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De Petrocellis et al 2002

Fundam Clin Pharmacol. 2002 Aug;16(4):297-302.

Links

Effect on cancer cell proliferation of palmitoylethanolamide, a fatty acid amide interacting with both the cannabinoid and vanilloid signalling systems.

De Petrocellis L, Bisogno T, Ligresti A, Bifulco M, Melck D, Di Marzo V.

Istituto di Cibernetica Eduardo Caianiello, Consiglio Nazionale delle Ricerche, Comprensorio Olivetti, Pozzuoli, Napoli, Italy.

Palmitoylethanolamide (PEA) is a bioactive fatty acid amide belonging to the class of N-acyl-ethanolamines (NAEs).

…..This compound has been known since the 1950s for its anti-inflammatory effects,

….but was re-discovered only after the finding that another NAE,

………arachidonoyl-ethanolamide (anandamide, AEA),

…..could act as an endogenous ligand of cannabinoid receptors.

Although a similar function for PEA has also been proposed, this compound does not activate the two cannabinoid receptor subtypes described to date.

…. PEA and AEA are co-synthesized by cells, and

…..PEA might act as an ‘entourage’ compound for AEA, i.e. as an endogenous enhancer of AEA biological actions.

Indeed, long-term treatment of human breast cancer cells (HBCCs) with PEA downregulates the expression of the enzyme responsible for AEA degradation,

…..the fatty acid amide hydrolase, thereby leading to an enhancement of AEA-induced, and cannabinoid CB1 receptor-mediated, cytostatic [Inhibiting or suppressing cellular growth and multiplication] effect on HBCCs.

Fighting breast cancer

AEA is also a full agonist for the receptors of another class of bioactive fatty acid amides, the N-acyl-vanillyl-amines (e.g. capsaicin and olvanil).

…..These sites of action are known as vanilloid receptors of type 1 (VR1).

…..PEA enhances the VR1-mediated effects of AEA

……and capsaicin on calcium influx into cells.

These ‘entourage’ effects of PEA might be attributable to modulation of VR1 activity, and could underlie the enhancement by PEA, described here for the first time, of the antiproliferative effects of VR1 receptor agonists.

See also:

Gastroenterology. 2003 Sep;125(3):677-87.

Links

Comment in:

Possible endocannabinoid control of colorectal cancer growth.

Ligresti A, Bisogno T, Matias I, De Petrocellis L, Cascio MG, Cosenza V, D’argenio G, Scaglione G, Bifulco M, Sorrentini I, Di Marzo V.

Endovannabinoid Research Group, Institute of Biomolecular Chemistry, Pozzuoli, Italy.

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Cannabinoids ameliorate pain and reduce disease pathology in cerulein-induced acute pancreatitis.

Michalski CW, Laukert T, Sauliunaite D, Pacher P, Bergmann F, Agarwal N, Su Y, Giese T, Giese NA, Bátkai S, Friess H, Kuner R.

Gastroenterology. 2007 May;132(5):1968-78. Epub 2007 Feb 21.

PMID: 17484889 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Abstract – Germany Michalski et al 2007

RESULTS: Patients with acute pancreatitis showed an up-regulation of cannabinoid receptors and elevated levels of endocannabinoids in the pancreas….

CONCLUSIONS: In humans, acute pancreatitis is associated with up-regulation of ligands as well as receptors of the endocannabinoid system in the pancreas. Furthermore, our results suggest a therapeutic potential for cannabinoids in abolishing pain associated with acute pancreatitis and in partially reducing inflammation and disease pathology in the absence of adverse side effects.

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BRAIN FUNCTION’ Immunohistochemical description of the endogenous cannabinoid system in the rat cerebellum and functionally related nuclei.

Suárez J, Bermúdez-Silva FJ, Mackie K, Ledent C, Zimmer A, Cravatt BF, de Fonseca FR.

J Comp Neurol. 2008 Aug 1;509(4):400-21.

PMID: 18521853 [PubMed – indexed for MEDLINE]

Related Articles

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ENDOCANNIBINOIDS FOUND IN BRAIN, NOT ONLY IN PERIPHERAL TISSUE

Onaivi 2006

Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB2 receptors in the brain.

Onaivi ES.

Neuropsychobiology. 2006;54(4):231-46. Epub 2007 Mar 15.

PMID: 17356307 [PubMed – indexed for MEDLINE]

Related Articles

From abstract:

CB2 FOUND IN BRAIN, NOT ONLY IN PERIPHERY

For over a decade, until recently, it was thought that marijuana acts by activating brain-type cannabinoid receptors called CB1,

….. and that a second type called CB2 cannabinoid receptor was found only in peripheral tissues.

Neuronal CB2 receptors in the brain had been controversial. We reported the discovery and functional presence of CB2 cannabinoid receptors in the mammalian brain that may be involved in depression and drug abuse and this was supported by reports of identification of neuronal CB2 receptors that are involved in emesis [vomiting]. RT-PCR, immunoblotting, hippocampal cultures, immunohistochemistry, transmission electron microscopy, and stereotaxic techniques with behavioral assays were used to determine the functional expression of CB2 cannabinoid receptors in the rat brain and mouse brain exposed to chronic mild stress or treated with abused drugs. RT-PCR analyses supported the expression of brain CB2 receptor transcripts at levels much lower than those of CB1 receptors. In situ hybridization revealed

CB2 mRNA in cerebellar neurons of wild-type but not of CB2 knockout mice. Abundant CB2 receptor immunoreactivity (iCB2) in neuronal and glial processes was detected in the brain. The effect of direct CB2 antisense oligonucleotide injection into the brain and treatment with JWH015 in motor function and plus-maze tests also demonstrated the functional presence of CB2 cannabinoid receptors in the central nervous system.

In humans, there was a high incidence of Q63R polymorphism in the CB2 gene in Japanese alcoholics and depressed subjects.

…..Contrary to the prevailing view that CB2 cannabinoid receptors are restricted to peripheral tissues and predominantly in immune cells, we demonstrated that CB2 cannabinoid receptors and their gene transcripts are widely distributed in the brain.

……This multifocal expression of iCB2 in the brain suggests that CB2 receptors may play broader roles than previously anticipated and may therefore be exploited as new targets in the treatment of depression and substance abuse

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[Interesting so much of the research mentions addiction in their conclusions.  I expect that funding streams and sources are connected mostly to this theme.]

Chiang et al 2004

Hum Mol Genet. 2004 Sep 15;13(18):2113-9. Epub 2004 Jul 14.

Links

Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use.

Chiang KP, Gerber AL, Sipe JC, Cravatt BF.

The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA.

Fatty acid amide hydrolase (FAAH) inactivates the endogenous cannabinoid (endocannabinoid) anandamide and related lipid transmitters in vivo. A single nucleotide polymorphism (SNP) in the human FAAH gene (385C to A) has recently been described that, in homozygous form, is over-represented in subjects with problem drug use. This SNP, which converts a conserved proline residue in FAAH to threonine (P129T), suggests a potential role for the FAAH-endocannabinoid system in regulating addictive behavior. Nonetheless, the impact of the 385A mutation on the biochemical and cellular function of FAAH remains unknown.

Here, we report that T-lymphocytes isolated from patients homozygous for the P129T-FAAH variant express less than half of the FAAH protein and activity observed in wild-type (WT) lymphocytes. Transfected COS-7 cells also expressed significantly lower levels of P129T-FAAH compared with WT-FAAH, indicating that the aberrant expression of the former protein is not a cell type-specific phenomenon. A comparison of the transcription/translation efficiencies and cellular stabilities of WT- and P129T-FAAH proteins revealed that the reduced expression of the mutant enzyme is due to a post-translational mechanism that precedes productive folding. These findings indicate that the natural 385A SNP in the human FAAH gene produces a mutant enzyme with reduced cellular stability, thus fortifying a potential link between functional abnormalities in the endocannabinoid system and drug abuse and dependence.

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Haring et al 2007

Neuroscience. 2007 May 25;146(3):1212-9. Epub 2007 Mar 23.

Links

Identification of the cannabinoid receptor type 1 in serotonergic cells of raphe nuclei in mice.

Häring M, Marsicano G, Lutz B, Monory K.

Department of Physiological Chemistry, Johannes Gutenberg University, Duesbergweg 6, 55099 Mainz, Germany.

The endocannabinoid system (ECS) possesses neuromodulatory functions by influencing the release of various neurotransmitters, including

GABA,

noradrenaline,

dopamine,

glutamate and acetylcholine.

Even though there are studies indicating similar interactions between the ECS and the serotonergic system, there are no results showing clear evidence for type 1 cannabinoid receptor (CB1) location on serotonergic neurons. In this study, we show by in situ hybridization that a low but significant fraction of serotonergic neurons in the raphe nuclei of mice contains CB1 mRNA as illustrated by the coexpression with the serotonergic marker gene tryptophane hydroxylase 2, the rate limiting enzyme for the serotonin synthesis. Furthermore, by double immunohistochemistry and confocal microscopy, we were able to

detect CB1 protein on serotonergic fibers and synapses expressing the serotonin uptake transporter in the hippocampus and the amygdala.

Our findings indicate that the

CB1-mediated regulation of serotonin release

can depend in part on a direct cross-talk

between the two systems at single cell level,

which might lead to functional implications

in the modulation of emotional states.

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[While the following talks about addiction, it is relevant to neurotransmitters in general]

Addict Biol. 2008 Jun;13(2):160-87. Epub 2008 Apr 16.

Links

The pharmacology of the endocannabinoid system: functional and structural interactions with other neurotransmitter systems and their repercussions in behavioral addiction.

López-Moreno JA, González-Cuevas G, Moreno G, Navarro M.

Department of Psychobiology, Faculty of Psychology, Campus de Somosaguas, Complutense University of Madrid, Spain. jalopezm@psi.ucm.es

Addiction is a chronic, recurring and complex disorder. It is characterized by anomalous behaviors that are linked to permanent or long-lasting neurobiological alterations. Furthermore, the endocannabinoid system has a crucial role in mediating neurotransmitter release as one of the main neuromodulators of the mammalian central nervous system.

The purpose of the present review is to instruct readers about the functional and structural interactions between the endocannabinoid system and the main neurotransmitter systems of the central nervous system in the context of drug addiction. With this aim, we have systematically reviewed the main findings of most of the existing literature that explores cross-talk in the five brain areas that are most traditionally implicated in addiction: amygdala, prefrontal cortex, nucleus accumbens, hippocampus and ventral tegmental area (VTA). The neurotransmission systems influenced by the pharmacology of the endocannabinoid system in these brain areas, which are reviewed here, are gamma-aminobutyric acid (GABA), glutamate, the main biogenic amines (dopamine, noradrenaline and serotonin), acetylcholine and opioids. We show that all of these neurotransmitter systems can be modulated differentially in each brain area by the activation or deactivation of cannabinoid CB1 brain receptors. Specifically, most of the studies relate to the hippocampus and nucleus accumbens. Moreover, the neurotransmitter with the fewest number of related studies is acetylcholine (excepting in the hippocampus), whereas there is a large number that evaluates GABA, glutamate and dopamine. Finally, we propose a possible interpretation of the role of the endocannabinoid system in the phenomenon of addiction.

PMID: 18422831 [PubMed – indexed for MEDLINE

++++++

Melis et al 2004

J Neurosci. 2004 Jan 7;24(1):53-62.

Links

Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors.

Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, Gessa GL.

Centre of Excellence, Neurobiology of Addiction, University of Cagliari, Monserrato, 09042 Italy. myriam@unica.it

The endogenous cannabinoid system has been shown to play a crucial role in controlling neuronal excitability and synaptic transmission. In this study we investigated the effects of a cannabinoid receptor (CB-R) agonist WIN 55,212-2 (WIN) on excitatory synaptic transmission in the rat ventral tegmental area (VTA). Whole-cell patch clamp recordings were performed from VTA dopamine (DA) neurons in an in vitro slice preparation. WIN reduced both NMDA and AMPA EPSCs, as well as miniature EPSCs (mEPSCs), and increased the paired-pulse ratio, indicating a presynaptic locus of its action. We also found that WIN-induced effects were dose-dependent and mimicked by the CB1-R agonist HU210. Furthermore, two CB1-R antagonists, AM281 and SR141716A, blocked WIN-induced effects, suggesting that WIN modulates excitatory synaptic transmission via activation of CB1-Rs. Our additional finding that both AM281 and SR141716A per se increased NMDA EPSCs suggests that endogenous cannabinoids, released from depolarized postsynaptic neurons, might act retrogradely on presynaptic CB1-Rs to suppress glutamate release. Hence, we report that a type of synaptic modulation, previously termed depolarization-induced suppression of excitation (DSE), is present also in the [ventral tegmental area] VTA as a calcium-dependent phenomenon, blocked by both AM281 and SR141716A, and occluded by WIN. Importantly, DSE was partially blocked by the D2DA antagonist eticlopride and enhanced by the D2DA agonist quinpirole without changing the presynaptic cannabinoid sensitivity. These results indicate that the

two pathways

work in a cooperative manner

to release endocannabinoids in the VTA,

where they play a role as retrograde messengers for DSE via CB1-Rs

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Lopez-Moreno et al 2008

Addict Biol. 2008 Jun;13(2):160-87. Epub 2008 Apr 16.

Links

The pharmacology of the endocannabinoid system: functional and structural interactions with other neurotransmitter systems and their repercussions in behavioral addiction.

López-Moreno JA, González-Cuevas G, Moreno G, Navarro M.

Department of Psychobiology, Faculty of Psychology, Campus de Somosaguas, Complutense University of Madrid, Spain. jalopezm@psi.ucm.es

Addiction is a chronic, recurring and complex disorder. It is characterized by anomalous behaviors that are linked to permanent or long-lasting neurobiological alterations. Furthermore, the

endocannabinoid system has a crucial role in mediating neurotransmitter release as one of the main neuromodulators of the mammalian central nervous system.

The purpose of the present review is to instruct readers about the functional and structural interactions between the endocannabinoid system and the main neurotransmitter systems of the central nervous system in the context of drug addiction. With this aim, we have systematically reviewed the main findings of most of the existing literature that

explores cross-talk in the five brain areas that are most traditionally implicated in addiction:

amygdala, p

refrontal cortex,

nucleus accumbens,

hippocampus and

ventral tegmental area (VTA).

The neurotransmission systems influenced by the pharmacology of the endocannabinoid system in these brain areas, which are reviewed here, are gamma-aminobutyric acid (GABA),

glutamate, the

main biogenic amines (dopamine, noradrenaline and serotonin),

acetylcholine and

opioids.

We show that all of

these neurotransmitter systems can be modulated differentially i

n each brain area by the activation or deactivation

of cannabinoid CB1 brain receptors.

Specifically, most of the studies relate to the hippocampus and nucleus accumbens. Moreover, the neurotransmitter with the fewest number of related studies is acetylcholine (excepting in the hippocampus), whereas there is a large number that evaluates GABA, glutamate and dopamine. Finally, we propose a possible interpretation of the role of the endocannabinoid system in the phenomenon of addiction.

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Neurobiol Dis. 2006 Oct;24(1):15-27. Epub 2006 Jun 8.

Links

Protective activation of the endocannabinoid system during ischemia in dopamine neurons.

Melis M, Pillolla G, Bisogno T, Minassi A, Petrosino S, Perra S, Muntoni AL, Lutz B, Gessa GL, Marsicano G, Di Marzo V, Pistis M.

Centre of Excellence Neurobiology of Addiction, University of Cagliari, Italy. myriam@unica.it

Endocannabinoids act as neuroprotective molecules promptly released in response to pathological stimuli. Hence, they may represent one component of protection and/or repair mechanisms mobilized by dopamine (DA) neurons under ischemia. Here, we show that the endocannabinoid 2-arachidonoyl-glycerol (2-AG) plays a key role in protecting DA neurons from ischemia-induced altered spontaneous activity both in vitro and in vivo. Accordingly, neuroprotection can be elicited through moderate cannabinoid receptor type-1 (CB1) activation. Conversely, blockade of endocannabinoid actions through CB1 receptor antagonism worsens the outcome of transient ischemia on DA neuronal activity. These findings indicate that 2-AG mediates neuroprotective actions by delaying damage and/or restoring function of DA cells through activation of presynaptic CB1 receptors. Lastly, they point to CB1 receptors as valuable targets in protection of DA neurons against ischemic injury and emphasize the need for a better understanding of endocannabinoid actions in the fine control of DA transmission.

PMID: 16762556 [PubMed – indexed for MEDLINE

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Steiner et al 2008

Psychoneuroendocrinology. 2008 Sep;33(8):1165-70. Epub 2008 Jul 23.

Links

Conditional cannabinoid receptor type 1 mutants reveal neuron subpopulation-specific effects on behavioral and neuroendocrine stress responses.

Steiner MA, Marsicano G, Wotjak CT, Lutz B.

Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany. michel.steiner@actelion.com

The complete genetic loss or pharmacological blockade of cannabinoid receptor type 1 (CB1) in mice results in both altered behavioral performance and increased stress hormone secretion in response to stressful encounters such as forced swim test (FST) exposure.

CB1 is expressed on nerve terminals belonging to different neurotransmitter systems, including the glutamatergic and GABAergic system, where it is able to suppress excitatory and inhibitory neurotransmission, respectively.

In the current study, we used the conditional mutagenesis approach in mice to investigate the neurotransmitter systems involved in these

behavioral and neuroendocrine phenotypes in regard to CB1 signaling.

Mice lacking CB1 in cortical glutamatergic neurons (Glu-CB1(-/-)) showed decreased passive stress coping (decreased immobility) in the FST, whereas mice lacking CB1 in principal forebrain neurons (CaMK-CB1(-/-)) and GABAergic neurons (GABA-CB1(-/-)), respectively, behaved as littermate controls. However, we found increased FST-induced corticosterone secretion only in CaMK-CB1(-/-) mice, whereas Glu-CB1(-/-) and GABA-CB1(-/-) mice exhibited normal corticosterone release as compared to controls. Thus,

behavioral and neuroendocrine acute stress coping

in response to the FST [stressor] is mainly influenced by

CB1 signaling on different glutamatergic neuronal subpopulations,

but not by CB1 on GABAergic neurons.

See also:

Psychoneuroendocrinology. 2008 Jan;33(1):54-67. Epub 2007 Oct 31.

Links

Antidepressant-like behavioral effects of impaired cannabinoid receptor type 1 signaling coincide with exaggerated corticosterone secretion in mice.

Steiner MA, Marsicano G, Nestler EJ, Holsboer F, Lutz B, Wotjak CT.

Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany. steinmi@uni-mainz.de

Pharmacogenomics J. 2008 Jun;8(3):196-208. Epub 2007 Aug 7.

Links

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice.

Steiner MA, Wanisch K, Monory K, Marsicano G, Borroni E, Bächli H, Holsboer F, Lutz B, Wotjak CT.

Max Planck Institute of Psychiatry, Munich, Germany. steiner@mpipsykl.mpg.de

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CELL GROWTH

Derocq et al 1998

FEBS Lett. 1998 Apr 3;425(3):419-25.

Links

The endogenous cannabinoid anandamide is a lipid messenger activating cell growth via a cannabinoid receptor-independent pathway in hematopoietic cell lines.

Derocq JM, Bouaboula M, Marchand J, Rinaldi-Carmona M, Ségui M, Casellas P.

Sanofi Recherche, Montpellier, France. jean-marie.derocq@tls1.elfsanofi.fr

The effect of anandamide, an endogenous ligand for central (CB1) and peripheral (CB2) cannabinoid receptors,

……….was investigated on the growth of the murine IL-6-dependent lymphoid cell line B9

……….and the murine IL-3-dependent myeloblastic cell line FDC-P1.

………In conditions of low serum [the clear liquid which separates from the blood when it is allowed to clot] level, anandamide potentiated the growth of both cytokine-dependent cell lines.

…a very similar effect, suggesting that cell growth enhancement by anandamide or its analogs could be mediated through either receptor subtype.

However, several lines of evidence indicated that this growth-promoting effect was cannabinoid receptor-independent.

……..First, the potent synthetic cannabinoid agonist CP 55940, which displays high affinity for both receptors, was inactive in this model.

…….Second, SR 141716A and SR 144528, which are potent and specific antagonists of CB1 and CB2 receptors respectively, were unable, alone or in combination, to block the anandamide-induced effect.

……..Third, inactivation of both receptors by pretreatment of cells with pertussis toxin did not affect the potentiation of cell growth by anandamide.

These data demonstrated that neither CB1 nor CB2 receptors were involved in the anandamide-induced effect. Moreover, using CB2-transfected Chinese hamster ovary cells, we demonstrated that after complete blockade of the receptors by the specific antagonist SR 144528, anandamide was still able to strongly stimulate a mitogen-activated protein (MAP) kinase activity, clearly indicating that the endogenous cannabinoid can transduce a mitogenic signal in the absence of available receptors.

Finally, arachidonic acid, a structurally related compound and an important lipid messenger without known affinity for cannabinoid receptors, was shown to trigger MAP kinase activity and cell growth enhancement similar to those observed with anandamide. These findings provide clear evidence for a functional role of anandamide in activating a signal transduction pathway leading to cell activation and proliferation via a non-cannabinoid receptor-mediated process.

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Reggio & Traore 2000

Chem Phys Lipids. 2000 Nov;108(1-2):15-35.

Links

Conformational requirements for endocannabinoid interaction with the cannabinoid receptors, the anandamide transporter and fatty acid amidohydrolase.

Reggio PH, Traore H.

Department of Chemistry, Kennesaw State University, 1000 Chastain Road, Kennesaw, GA 30144, USA. preggio@kennesaw.edu

Anandamide (N-arachidonoylethanolamine) has been identified as an endogenous ligand of the G-protein coupled cannabinoid CB(1) receptor. ……..Recent studies have postulated the existence of carrier-mediated anandamide transport which is involved in the termination of the biological effects of anandamide.

………A membrane bound amidohydrolase (fatty acid amide hydrolase, FAAH), located intracellulary, hydrolyzes and inactivates anandamide and other endogenous cannabinoids such as 2-arachidonoylglycerol (2-AG).

……..Structure-activity relationships (SARs) for endocannabinoid interaction with the CB receptors, the anandamide transporter and FAAH are currently emerging in the literature. This review considers the divergences between these SARs and focuses upon the conformational implications for endocannabinoid recognition at each of these biological targets.

See also:

Curr Pharm Des. 2000 Sep;6(13):1381-97.

Links

Natural and synthetic endocannabinoids and their structure-activity relationships.

Palmer SL, Khanolkar AD, Makriyannis A.

Departments of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.

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Samson et al 2003

J Immunol. 2003 May 15;170(10):4953-62.

Links

Comment in:

J Immunol. 2003 Sep 15;171(6):2767.

Differential roles of CB1 and CB2 cannabinoid receptors in mast cells.

Samson MT, Small-Howard A, Shimoda LM, Koblan-Huberson M, Stokes AJ, Turner H.

Laboratory of Cell Biology and Immunology, Queen’s Center for Biomedical Research, Queen’s Medical Center, Honolulu, HI 96813, USA.

Cannabinoid

modulation of immune responses

……is a pathological consequence of marijuana abuse and a potential outcome of therapeutic application of the drug.

Moreover, endogenous cannabinoids are physiological immune regulators.

In the present report, we describe alterations in gene transcription that occur after cannabinoid exposure in a mast [cells, which synthesize and store histamines, found in most body tissues] cell line, RBL2H3.

Cannabinoid exposure causes marked changes in the transcript levels for numerous genes, acting both independently of and in concert with immunoreceptor stimulation via Fc epsilon RI.

In two mast cell lines, we observed mRNA and protein expression corresponding to both CB1 and CB2 cannabinoid receptor isoforms,

………contrary to the prevailing view that CB1 is restricted to the CNS.

We show that coexpression of the two isoforms is not functionally redundant in mast cells.

…..Analysis of signaling pathways downstream of cannabinoid application reveals that activation of extracellular signal-regulated kinase, AKT, and a selected subset of AKT targets is accomplished by CB2 ligands and nonselective CB1/CB2 agonists in mast cells.

…..CB1 inhibition does not affect AKT or extracellular signal-regulated kinase activation by cannabinoids,

…..indicating that CB2 is the predominant regulatory receptor for these kinases in this cell context. .

…..CB1 receptors are, however, functional in these mast cells, since they can contribute to suppression of secretory responses.

See also:

J Immunol. 2003 May 15;170(10):4953-62.

Links

Differential roles of CB1 and CB2 cannabinoid receptors in mast cells.

Samson MT, Small-Howard A, Shimoda LM, Koblan-Huberson M, Stokes AJ, Turner H.

Laboratory of Cell Biology and Immunology, Queen’s Center for Biomedical Research, Queen’s Medical Center, Honolulu, HI 96813, USA.

Br J Pharmacol. 2007 Nov;152(5):624-32. Epub 2007 Aug 20.

Links

Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain.

Jhaveri MD, Richardson D, Chapman V.

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Dainese, Gasperi & Maccarrone 2005

Curr Drug Targets CNS Neurol Disord. 2005 Dec;4(6):709-14.

Links

Partial QSAR analysis of some selected natural inhibitors of FAAH suggests a working hypothesis for the development of endocannabinoid-based drugs.

Dainese E, Gasperi V, Maccarrone M.

Department of Biomedical Sciences, University of Teramo, Piazza Aldo Moro 45, 64100 Teramo, Italy.

The endogenous cannabinoids (endocannabinoids)

…are bioactive signaling molecules,

…that show diverse cellular and physiological effects and play various roles in the central nervous system, as well as in the periphery.

The discovery of N-arachidonoylethanolamine (anandamide, AEA)

….and of the enzyme that terminates its signaling, i. e. fatty acid amide hydrolase (FAAH),

….has inspired pharmacological strategies

…to augment endocannabinoid tone and biological activity through inhibition of FAAH.

Here we discuss the role of natural endocannabinoid derivatives,

…..like the hydroxy-anandamides (OH-AEAs) generated from AEA via lipoxygenase activity,

…..as powerful inhibitors of FAAH.

…..suggest that they could act at different specific sites

of FAAH,

thus confirming their potential value as templates for the development of next-generation therapeutics.

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Fezza et al 2008

Subcell Biochem. 2008;49:101-32.

Links

Fatty acid amide hydrolase: a gate-keeper of the endocannabinoid system.

Fezza F, De Simone C, Amadio D, Maccarrone M.

Department of Experimental Medicine and Biochemical Sciences, University of Rome, Rome, Italy.

The family of endocannabinoids

….contains several polyunsaturated fatty acid amides such as

….anandamide (AEA),

….but also esters such as 2-arachidonoylglycerol (2-AG).

These compounds are the main endogenous agonists of cannabinoid receptors,

…..able to mimic several pharmacological effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC),

…..the active principle of Cannabis sativa preparations like hashish and marijuana.

Isn’t the mimicry the other way around, folks???

The activity of AEA at its receptors is limited by cellular uptake,

….through a putative membrane transporter, I don’t think they’ve found

followed by intracellular degradation by fatty acid amide hydrolase (FAAH).

Growing evidence demonstrates that FAAH is the critical regulator of the endogenous levels of AEA,

suggesting that it may serve as an attractive therapeutic target for the treatment of human disorders.

……….In particular, FAAH inhibitors

….may be next generation therapeutics of potential value for the treatment of pathologies

….of the central nervous system,

….and of peripheral tissues.

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Hill et al 2008b

J Neurochem. 2008 Sep;106(6):2322-36. Epub 2008 Jul 15.

Links

Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment.

Hill MN, Carrier EJ, McLaughlin RJ, Morrish AC, Meier SE, Hillard CJ, Gorzalka BB.

Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada.

It has been suggested that disturbances in endocannabinoid signaling contribute to the development of depressive illness; however, at present there is insufficient evidence to allow for a full understanding of this role. To further this understanding, we performed an analysis of the endocannabinoid system in an animal model of depression. Male rats exposed to chronic, unpredictable stress (CUS) for 21 days exhibited a reduction in sexual motivation, consistent with the hypothesis that CUS in rats induces depression-like symptoms. We determined the effects of CUS, with or without concurrent treatment with the antidepressant imipramine (10 mg/kg), on CP55940 binding to the cannabinoid CB(1) receptor; whole tissue endocannabinoid content; and fatty acid amide hydrolase (FAAH) activity in the prefrontal cortex, hippocampus, hypothalamus, amygdala, midbrain and ventral striatum.

Exposure to chronic, unpredictable stress (CUS) resulted in a significant increase in CB(1) receptor binding site density in the prefrontal cortex and a decrease in CB(1) receptor binding site density in the hippocampus, hypothalamus and ventral striatum.

Except in the hippocampus, these chronic, unpredictable stress (CUS) -induced alterations in CB(1) receptor binding site density were attenuated by concurrent antidepressant treatment.

chronic, unpredictable stress (CUS) alone produced a significant reduction in N-arachidonylethanolamine (anandamide) content in every brain region examined, which was not reversed by antidepressant treatment.

These data suggest that

the endocannabinoid system in cortical and subcortical structures is differentially altered in an animal model of depression and that the effects of chronic, unpredictable stress (CUS) on CB(1) receptor binding site density are attenuated by antidepressant treatment while those on endocannabinoid content are not.

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LEARNING

Kishimoto & Kano 2006

J Neurosci. 2006 Aug 23;26(34):8829-37.

Links

Endogenous cannabinoid signaling through the CB1 receptor is essential for cerebellum-dependent discrete motor learning.

Kishimoto Y, Kano M.

Department of Cellular Neuroscience, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan

Cannabinoids exert their psychomotor actions through the CB1 cannabinoid receptor in the brain. Genetic deletion of CB1 in mice causes various symptoms, including changes in locomotor activity, increased ring catalepsy, supraspinal hypoalgesia, and impaired memory extinction.

Although the cerebellar cortex contains the highest level of CB1, severe cerebellum-related functional deficits have not been reported in CB1 knock-out mice. To clarify the roles of CB1 in cerebellar function, [this would implicate cognition, as well, both connected to this brain area] we subjected CB1 knock-out mice to a delay version of classical eyeblink conditioning. This paradigm is a test for cerebellum-dependent discrete motor learning, in which conditioned stimulus (CS) (352 ms tone) and unconditioned stimulus (US) (100 ms periorbital electrical shock) are coterminated. We found that delay eyeblink conditioning performance was severely impaired in CB1 knock-out mice. In contrast, they exhibited normal performance in a trace version of eyeblink conditioning with 500 ms stimulus-free interval intervened between the CS offset and the US onset. This paradigm is a test for hippocampus-dependent associative learning. Sensitivity of CB1 knock-out mice to CS or US was normal, suggesting that impaired delay eyeblink conditioning is attributable to defects in association of responses to CS and US. We also found that intraperitoneal injection of the CB1 antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole carboxamide] to wild-type mice caused severe impairment in acquisition but not extinction of delay eyeblink conditioning. SR141716A treatment had no effect on trace eyeblink conditioning with a 500 or 750 ms trace interval. These results indicate that

endogenous cannabinoid signaling through CB1 is essential for cerebellum-dependent discrete motor learning, especially for its acquisition.

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A search of the pubmed database for the terms “motor activity cannabinoid” brings up 665 articles.

+++++++++++++++++++++

Rodriguez et al 1998

Neurobiol Dis. 1998 Dec;5(6 Pt B):483-501.

Links

Role of the endogenous cannabinoid system in the regulation of motor activity.

Rodríguez de Fonseca F, Del Arco I, Martín-Calderón JL, Gorriti MA, Navarro M.

Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid, Spain. pspsc10@sis.ucm.es

One of the prominent pharmacological features of drugs acting at the brain cannabinoid receptor (CB1) is the induction of alterations in motor behavior.

Catalepsy, immobility, ataxia, or the impairment of complex behavioral acts are observed after acute administration of either natural and synthetic cannabinoid receptor agonists or the endogenous CB1 ligand anandamide.

The dense presence of CB1 receptors in the cerebellum and in the basal ganglia, especially at the outflow nuclei (substantia nigra and the internal segment of the globus pallidus),

supports the existence of an endogenous cannabinoid system regulating motor activity.

In the basal ganglia, the functionality of the anandamide-CB1 system is poorly understood.

Dual effects are often observed after the administration of CB1 ligands in animal models of pharmacological

…manipulation of basal ganglia transmitter systems,

….indicating that the activity of the anandamide-CB1 system

……depends on the ongoing activation of the different elements of the basal ganglia.

This finding is in agreement with the proposed activity-dependent release of anandamide from a plasmalemma precursor.

……….Additionally, a potential state-dependent bidirectional coupling

…. of the CB1 receptor

……to the adenylate cyclase transduction system has also been described.

From this perspective, the

endogenous cannabinoid system can be proposed as a local regulator of neurotransmission processes within the basal ganglia.

This system may serve as a counterregulatory homeostatic mechanism preserving the functional role of basal ganglia circuits in coding the serial order of events that constitute movement.

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see also:

Kawamura et al 2006

Abstract – Department of Cellular Neuroscience, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan.

Endocannabinoids work as retrograde messengers and contribute to short-term and long-term modulation of synaptic transmission via presynaptic cannabinoid receptors.

It is generally accepted that the CB1 cannabinoid receptor (CB1) mediates the effects of endocannabinoid in inhibitory synapses. For excitatory synapses, however, contributions of CB1, “CB3,” and some other unidentified receptors have been suggested. In the present study we used electrophysiological and immunohistochemical techniques and examined the type(s) of cannabinoid receptor functioning at hippocampal and cerebellar excitatory synapses.

Our electrophysiological data clearly demonstrate the predominant contribution of CB1. At hippocampal excitatory synapses on pyramidal neurons the cannabinoid-induced synaptic suppression was reversed by a CB1-specific antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), and was absent in CB1 knock-out mice. At climbing fiber (CF) and parallel fiber (PF) synapses on cerebellar Purkinje cells the cannabinoid-dependent suppression was absent in CB1 knock-out mice. The presence of CB1 at presynaptic terminals was confirmed by immunohistochemical experiments with specific antibodies against CB1. In immunoelectron microscopy the densities of CB1-positive signals in hippocampal excitatory terminals and cerebellar PF terminals were much lower than in inhibitory terminals but were clearly higher than the background. Along the long axis of PFs, the CB1 was localized at a much higher density on the perisynaptic membrane than on the extrasynaptic and synaptic regions. In contrast, CB1 density was low in CF terminals and was not significantly higher than the background. Despite the discrepancy between the electrophysiological and morphological data for CB1 expression on CFs, these results collectively indicate that

CB1 is responsible for cannabinoid-dependent suppression of excitatory transmission in the hippocampus and cerebellum.

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Marchalant et al 2008

Neurobiol Aging. 2008 Dec;29(12):1894-901. Epub 2007 Jun 11.

Links

Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats.

Marchalant Y, Cerbai F, Brothers HM, Wenk GL.

Department of Psychology, Psychology Building, Ohio State University, Columbus, OH 43210, USA. marchalant.1@osu.edu

The number of activated microglia increase during normal aging. Stimulation of endocannabinoid receptors can reduce the number of activated microglia, particularly in the hippocampus, of young rats infused chronically with lipopolysaccharide (LPS). In the current study we demonstrate that endocannabinoid receptor stimulation by administration of WIN-55212-2 (2mg/kg day) can reduce the number of activated microglia in hippocampus of aged rats and attenuate the spatial memory impairment in the water pool task. Our results suggest that the action of WIN-55212-2 does not depend upon a direct effect upon microglia or astrocytes but is dependent upon stimulation of neuronal cannabinoid receptors. Aging significantly reduced cannabinoid type 1 receptor binding but had no effect on cannabinoid receptor protein levels. Stimulation of cannabinoid receptors may provide clinical benefits in age-related diseases that are associated with brain inflammation, such as Alzheimer’s disease.

PMID: 17561311 [PubMed – indexed for MEDLINE]

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Neuroscience. 2007 Feb 23;144(4):1516-22. Epub 2006 Dec 18.

Links

Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation.

Marchalant Y, Rosi S, Wenk GL.

Arizona Research Laboratories, Division of Neural Systems Memory and Aging, University of Arizona, Tucson, AZ, USA.

Cannabinoid receptors (CBr) stimulation induces numerous central and peripheral effects. A growing interest in the beneficial properties of manipulating the endocannabinoid system has led to the possible involvement of CBr in the control of brain inflammation. In the present study we examined the effect of the CBr agonist, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4benzoxazin-6-yl]-1-naphthalenyl-methanone mesylate (WIN-55212-2), on microglial activation and spatial memory performance, using a well-characterized animal model of chronic brain inflammation produced by the infusion of lipopolysaccharide (LPS, 250 ng/h for 3 weeks) into the fourth ventricle of young rats. WIN-55212-2 (0.5 or 1.0 mg/kg/day, i.p.) was administered for 3 weeks. During the third week of treatment, spatial memory ability was examined using the Morris water-maze task. We found that 0.5 and 1 mg/kg WIN-55212-2 reduced the number of LPS-activated microglia, while 1 mg/kg WIN-55212-2 potentiated the LPS-induced impairment of performance in the water maze task. Cannabinoid receptors 1 were not expressed by microglia and astrocytes, suggesting an indirect effect of WIN-55212-2 on microglia activation and memory impairment. Our results emphasize the potential use of CBr agonists in the regulation of inflammatory processes within the brain; this knowledge may lead to the use of CBr agonists in the treatment of neurodegenerative diseases associated with chronic neuroinflammation, such as Alzheimer disease.

PMID: 17178196 [PubMed – indexed for MEDLINE]

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Hashimotodani, Ohno-Shosaku & Kano 2007

Neuroscientist. 2007 Apr;13(2):127-37.

Links

Endocannabinoids and synaptic function in the CNS.

Hashimotodani Y, Ohno-Shosaku T, Kano M.

Department of Neurophysiology, Graduate School of Medicine, Osaka University, Suita, Japan.

Marijuana affects neural functions through the binding of its active component (Delta(9)-THC) to cannabinoid receptors in the CNS.

Recent studies have elucidated that endogenous ligands for cannabinoid receptors, endocannabinoids, serve as retrograde messengers at central synapses. Endocannabinoids are produced on demand in

activity-dependent

manners and released from postsynaptic neurons.

The released endocannabinoids

travel backward across the synapse,

activate presynaptic CB1 cannabinoid receptors,

and modulate presynaptic functions.

Retrograde endocannabinoid signaling

is crucial for certain forms of short-term and long-term synaptic plasticity at excitatory or inhibitory synapses in many brain regions,

and thereby contributes to various aspects of brain function

including learning and memory.

Molecular identities of the CB1 receptor and enzymes involved in production and degradation of endocannabinoids have been elucidated. Anatomical studies have demonstrated

unique distributions of these molecules around synapses,

which provide morphological bases for the

roles of endocannabinoids as

retrograde messengers.

CB1-knockout mice exhibit various behavioral abnormalities and multiple defects in synaptic plasticity, supporting the notion that endocannabinoid signaling is involved in various aspects of neural function. In this review article, the authors describe molecular mechanisms of the endocannabinoid-mediated synaptic modulation and its possible physiological significance.

++++

See also:

Neuropsychopharmacology. 2009 Jan;34(2):509-21. Epub 2008 Jun 25.

Links

Functional interactions between endocannabinoid and CCK neurotransmitter systems may be critical for extinction learning.

Chhatwal JP, Gutman AR, Maguschak KA, Bowser ME, Yang Y, Davis M, Ressler KJ.

Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.

Mol Neurobiol. 2007 Aug;36(1):92-101. Epub 2007 Aug 17.

Links

The endocannabinoid system and extinction learning.

Lutz B.

Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 6, D-55099 Mainz, Germany. blutz@uni-mainz.de

Pharmacol Res. 2007 Nov;56(5):367-81. Epub 2007 Sep 8.

Links

The endocannabinoid system in the processing of anxiety and fear and how CB1 receptors may modulate fear extinction.

Lafenêtre P, Chaouloff F, Marsicano G.

Research Centre INSERM U862, AVENIR Team Molecular Mechanisms of Behavioural Adaptation, 146 rue Léo Saignat, 33700 Bordeaux, France.

Physiol Rev. 2009 Jan;89(1):309-80.

Links

Endocannabinoid-mediated control of synaptic transmission.

Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M.

Department of Neurophysiology, The University of Tokyo, Tokyo, Japan. mkano-tky@m.u-tokyo.ac.j

Pharmacological evidence for the involvement of diacylglycerol lipase in depolarization-induced endocanabinoid release.

Hashimotodani Y, Ohno-Shosaku T, Maejima T, Fukami K, Kano M.

Neuropharmacology. 2008 Jan;54(1):58-67. Epub 2007 Jun 22.

PMID: 17655882 [PubMed – indexed for MEDLINE]

Related Articles

Roles of phospholipase Cbeta and NMDA receptor in activity-dependent endocannabinoid release.

Hashimotodani Y, Ohno-Shosaku T, Watanabe M, Kano M.

J Physiol. 2007 Oct 15;584(Pt 2):373-80. Epub 2007 Jul 5.

PMID: 17615097 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Endocannabinoid signalling triggered by NMDA receptor-mediated calcium entry into rat hippocampal neurons.

Ohno-Shosaku T, Hashimotodani Y, Ano M, Takeda S, Tsubokawa H, Kano M.

J Physiol. 2007 Oct 15;584(Pt 2):407-18. Epub 2007 Jul 5.

PMID: 17615096 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus.

Hashimotodani Y, Ohno-Shosaku T, Kano M.

J Neurosci. 2007 Jan 31;27(5):1211-9.

PMID: 17267577 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

[Mechanisms of triggering endocannabinoid release]

Hashimotodani Y, Ohno-Shosaku T, Kano M.

Seikagaku. 2006 Feb;78(2):126-30. Japanese. No abstract available.

PMID: 16541803 [PubMed – indexed for MEDLINE]

Related Articles

Calcium signaling and synaptic modulation: regulation of endocannabinoid-mediated synaptic modulation by calcium.

Ohno-Shosaku T, Hashimotodani Y, Maejima T, Kano M.

Cell Calcium. 2005 Sep-Oct;38(3-4):369-74. Review.

PMID: 16085309 [PubMed – indexed for MEDLINE]

Related Articles

Synaptically driven endocannabinoid release requires Ca2+-assisted metabotropic glutamate receptor subtype 1 to phospholipase Cbeta4 signaling cascade in the cerebellum.

Maejima T, Oka S, Hashimotodani Y, Ohno-Shosaku T, Aiba A, Wu D, Waku K, Sugiura T, Kano M.

J Neurosci. 2005 Jul 20;25(29):6826-35.

PMID: 16033892 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

Phospholipase Cbeta serves as a coincidence detector through its Ca2+ dependency for triggering retrograde endocannabinoid signal.

Hashimotodani Y, Ohno-Shosaku T, Tsubokawa H, Ogata H, Emoto K, Maejima T, Araishi K, Shin HS, Kano M.

Neuron. 2005 Jan 20;45(2):257-68.

PMID: 15664177 [PubMed – indexed for MEDLINE]

Related Articles

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Chiu & Castillo 2008

Neuropharmacology. 2008 Jan;54(1):68-78. Epub 2007 Jul 6.

Links

Input-specific plasticity at excitatory synapses mediated by endocannabinoids in the dentate gyrus.

Chiu CQ, Castillo PE.

Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Endocannabinoids (eCBs) mediate transient and long-lasting synaptic plasticity in several brain structures.

In the dentate gyrus, activation of the type 1 cannabinoid receptor (CB1R) by exogenous ligands reportedly depresses excitatory synaptic transmission. However, direct evidence of eCB signaling at excitatory synapses in this region has been lacking. Here, we demonstrate that eCB release can be induced by a brief postsynaptic depolarization of dentate granule cells (DGCs), which potently and transiently suppresses glutamatergic inputs from mossy cell interneurons (MCs) but not from entorhinal cortex via the lateral and medial perforant paths. This input-specific depolarization-induced suppression of excitation (DSE) is calcium-dependent and can be modulated by agonists of cholinergic and group I metabotropic glutamate receptors. Inhibiting the synthesis of 2-arachidonoyl glycerol (2-AG), one of the most abundant eCBs in the brain, by diacyglycerol lipase (DGL) does not abolish DSE. Moreover, preventing the breakdown of anandamide, the other main eCB, does not potentiate DSE. Thus,

eCB signaling underlying DSE in the dentate does not require DGL activity and is unlikely to be mediated by anandamide.

Finally, we find that manipulations known to induce eCB-LTD at other central synapses do not trigger LTD at MCF-DGC synapses.

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Azad et al 2008

Learn Mem. 2008 Mar 5;15(3):143-52. Print 2008 Mar.

Links

Activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the lateral amygdala.

Azad SC, Kurz J, Marsicano G, Lutz B, Zieglgänsberger W, Rammes G.

Max-Planck-Institute of Psychiatry, Clinical Neuropharmacology, 80804 Munich, Germany. Shahnaz.Azad@med.uni-muenchen.de

Previously, we found that in the lateral amygdala (LA) of the mouse, WIN55,212-2 decreases both glutamatergic and GABAergic synaptic transmission via activation of the cannabinoid receptor type 1 (CB1), yet produces an overall reduction of neuronal excitability.

This suggests that the effects on excitatory transmission override those on inhibitory transmission. Here we show that CB1 activation by WIN55,212-2 and Delta(9)-THC inhibits long-term depression (LTD) of basal synaptic transmission in the LA, induced by low-frequency stimulation (LFS; 900 pulses/1 Hz). The CB1 agonist WIN55,212-2 blocked LTD via G(i/o) proteins, activation of inwardly rectifying K+ channels (K(ir)s), inhibition of the adenylate cyclase-protein kinase A (PKA) pathway, and PKA-dependent inhibition of voltage-gated N-type Ca2+ channels (N-type VGCCs). Interestingly, WIN55,212-2 effects on LTD were abolished in CB1 knock-out mice (CB1-KO), and in conditional mutants lacking CB1 expression only in GABAergic interneurons, but were still present in mutants lacking CB1 in principal forebrain neurons. LTD induction per se was unaffected by the CB1 antagonist SR141716A and was normally expressed in CB1-KO as well as in both conditional CB1 mutants. Our data demonstrate that

activation of CB1

specifically located on GABAergic interneurons

inhibits LTD in the LA. These findings suggest that

CB1 expressed on either glutamatergic or GABAergic neurons play a differential role in the control

of synaptic transmission and plasticity.

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Crit Rev Neurobiol. 2006;18(1-2):113-24.

Links

Endocannabinoid signaling and synaptic plasticity in the brain.

Zhu PJ.

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health and National Chemical Genomics Center, National Human Genome Research Institute, Bethesda, MD, USA. pzhu@mail.nih.gov

Repetitive firing neuron or activation of synaptic transmission plays an important role in the modulation of synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). These activity-dependent changes in synaptic efficacy are thought to be critical to learning and memory; however, the underlying mechanisms remain to be defined. Endogenous cannabinoids (eCBs) are diffusible modulators that are released from depolarized postsynaptic neurons and act on presynaptic terminals. Persistent release of eCBs can lead to long-term modulation of synaptic plasticity in the brain. Given a broad distribution of eCB receptors in the brain, the eCB signaling system could contribute to use-dependent modification of brain functions.

PMID: 17725514 [PubMed – indexed for MEDLINE

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Lovinger 2008

Handb Exp Pharmacol. 2008;(184):435-77.

Links

Presynaptic modulation by endocannabinoids.

Lovinger DM.

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, MD 20892-9411, USA. lovindav@mail.nih.gov

Modulation of neurotransmitter release by G-protein-coupled receptors (GPCRs) is a prominent presynaptic mechanism for regulation of synaptic transmission.

Activation of GPCRs located at the presynaptic terminal can decrease the probability of neurotransmitter release.

This presynaptic depression involves activation of Gi/o-type G-proteins that mediate different inhibitory mechanisms, including inhibition of voltage-gated calcium channels, activation of potassium channels, and direct inhibition of the vesicle fusion process.

A variety of neurotransmitters and modulatory agents can activate GPCRs that produce presynaptic depression. Among these are lipid metabolites that serve as agonists for GPCRs.

The discovery of endocannabinoids and their cognate receptors, including the CB1 receptor, has stimulated intense investigation into the neurophysiological roles of these lipid metabolites.

It is now clear that presynaptic depression is the major physiological role for the CB1 receptor.

Endocannabinoids activate this receptor mainly via a retrograde signaling process in which these compounds are synthesized in and released from postsynaptic neuronal elements,

and travel back to the presynaptic terminal to act on the CB1 receptor.

This retrograde endocannabinoid modulation has been implicated in short-term synaptic depression, including suppression of excitatory or inhibitory transmission induced by postsynaptic depolarization and transient synaptic depression induced by activation of postsynaptic GPCRs during agonist treatment or synaptic activation.

Endocannabinoids and the CB1 receptor also play a key role in one form of long-term synaptic depression (LTD) that involves a longlasting decrease in neurotransmitter release.

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Heifets, Chevaleyre & Castillo 2008

Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10250-5. Epub 2008 Jul 16.

Links

Interneuron activity controls endocannabinoid-mediated presynaptic plasticity through calcineurin.

Heifets BD, Chevaleyre V, Castillo PE.

Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Retrograde signaling by endocannabinoids (eCBs)

mediates a widely expressed form of long-term depression

at excitatory and inhibitory synapses (eCB-LTD),

involving a reduction in neurotransmitter release.

In the hippocampus, eCB-LTD occurs at interneuron (IN)-pyramidal cell (PC) synapses (I-LTD), and its induction requires a presynaptic reduction of cAMP/PKA signaling resulting from minutes of type 1 cannabinoid receptor (CB1R) activation.

Although repetitive activity of glutamatergic synapses initiates the eCB mobilization required for I-LTD, it is unclear whether CB1R-containing GABAergic terminals are passive targets of eCBs or whether they actively contribute to induction. Here, we show that the minutes-long induction period for I-LTD may serve as a window to integrate associated spontaneous activity….Our findings support a model where both CB1R signaling and interneuron (IN)-activity shift the balance of kinase and phosphatase activity in the presynaptic terminal to induce I-LTD.

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Vaughan & Christie 2005

Handb Exp Pharmacol. 2005;(168):367-83.

Links

Retrograde signalling by endocannabinoids.

Vaughan CW, Christie MJ.

Pain Management Research Institute, Northern Clinical School, University of Sydney at Royal North Shore Hospital, 2006 NSW, Sydney, Australia.

The cannabinoid neurotransmitter system comprises cannabinoid G protein-coupled membrane receptors (CB1 and CB2), endogenous cannabinoids (endocannabinoids), as well as mechanisms for their synthesis, membrane transport and metabolism. Within the brain the marijuana constituent delta9-tetrahydrocannabinol (THC) produces its pharmacological actions by acting on cannabinoid CB1 receptors. THC modulates neuronal excitability by inhibiting synaptic transmission via presynaptic CB1-mediated mechanisms.

More recently, it has been established that physiological stimulation of neurons can induce the synthesis of endocannabinoids, which also modulate synaptic transmission via cannabinoid CB1 and other receptor systems. These endogenously synthesized endocannabinoids appear to act as retrograde signaling agents,

reducing synaptic inputs onto the stimulated neuron in a highly selective and restricted manner.

In this review we describe the cellular mechanisms underlying retrograde endocannabinoid signaling.

See also:

J Neurosci. 2004 Nov 3;24(44):9953-61.

Links

Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling.

Azad SC, Monory K, Marsicano G, Cravatt BF, Lutz B, Zieglgänsberger W, Rammes G.

Clinical Neuropharmacology, Max-Planck-Institute of Psychiatry, 80804 Munich, Germany. azad@mpipsykl.mpg.de

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Oropeza, Mackie & Van Bockstaele 2007

Brain Res. 2007 Jan 5;1127(1):36-44. Epub 2006 Nov 17.

Links

Cannabinoid receptors are localized to noradrenergic axon terminals in the rat frontal cortex.

Oropeza VC, Mackie K, Van Bockstaele EJ.

Department of Neurosurgery, Thomas Jefferson University, Farber Institute for Neurosciences, 900 Walnut St., Suite 400, Philadelphia, PA 19107, USA.

Cannabinoid agonists exert complex actions on modulatory neurotransmitters involved in attention and cognition.

In an effort to elucidate whether cannabinoid (CB1) receptors are positioned to presynaptically modulate norepinephrine release in the frontal cortex,

… Ultrastructural analysis confirmed that one-third of axon terminals containing CB1 immunolabeling also exhibited DbetaH labeling.

….. Cortical neurons were also found to be targeted by separately labeled CB1- and DbetaH-containing axon terminals.

In conclusion, the present neuroanatomical data suggest that cortical norepinephrine release may be modulated,

in part,

by CB1 receptors that are presynaptically distributed on noradrenergic axon terminals.

++++++++++++++++

Elenkov et al 2000

Pharmacol Rev. 2000 Dec;52(4):595-638.

Links

The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system.

Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES.

Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.

IMPORTANT

The brain

and the immune system

are the two major adaptive systems of the body.

……..During an immune response

the brain and the immune system “talk to each other”

and this process is essential for maintaining homeostasis.

Two major pathway systems are involved in this cross-talk:

….the hypothalamic-pituitary-adrenal (HPA) axis

….and the sympathetic nervous system (SNS).

This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. …………Evidence accumulated over the last 20 years suggests that

norepinephrine (NE)

[Norepinephrine is both a hormone and a neurotransmitter. As a hormone, secreted by the adrenal gland, it works alongside epinephrine / adrenaline to give the body sudden energy in times of stress, known as the “fight or flight” response. As a neurotransmitter, it passes nerve impulses from one neuron to the next.

Medications that inhibit the reuptake of norepinephrine and serotonin may be effective to treat depression. In addition, some studies have found elevated norepinephrine levels in patients experiencing mania.]

fulfills the criteria for neurotransmitter/neuromodulator in lymphoid [tissue associated with the lymphatic system, including tonsils and adenoids] organs.

Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation.

Under stimulation, NE is released from the sympathetic nerve terminals in these organs,

…………and the target immune cells express adrenoreceptors.

Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine,

…….affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells.

Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest.

….. In addition, recent evidence is discussed that NE and epinephrine,

………..through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway,

………inhibit the production of type 1/proinflammatory cytokines,

…… such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells,

…….whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta.

……….Through this mechanism, systemically, endogenous catecholamines may

cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity.

See Hawks & Dove information

On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. ……………Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response,

………..through induction of neutrophil accumulation and stimulation of more specific humoral immune responses,

…………although systemically it may suppress Th1 responses, and,

……….thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages.

The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth.

…………..Finally, the pharmacological manipulation of the

sympathetic-immune interface

is reviewed with focus on new therapeutic strategies using

selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists

These are the ones I am going to review as implicated in the erasing of the emotional component of memory, with possibility of “intercepting” outcome of PTSD following a traumatic experience

and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.

++++++++++++++++

see also, is in fear section:

Endocrinology. 2007 Apr;148(4):1574-81. Epub 2006 Dec 28.

Links

Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function.

Cota D, Steiner MA, Marsicano G, Cervino C, Herman JP, Grübler Y, Stalla J, Pasquali R, Lutz B, Stalla GK, Pagotto U.

Group of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.

++++++++++++

See also:  Search “norepinephrine cannabinoid” at pubmed for 196 more articles such as

Int J Obes (Lond). 2009 Jun;33 Suppl 2:S18-24.

Links

The endocannabinoid system as a link between homoeostatic and hedonic pathways involved in energy balance regulation.

Di Marzo V, Ligresti A, Cristino L.

Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Pozzuoli (NA), Italy. vdimarzo@icmib.na.cnr.it

Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4579-80. Epub 2009 Mar 17.

Links

Comment on:

Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4888-93.

Endocannabinoids: The silent partner of glucocorticoids in the synapse.

Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4888-93. Epub 2009 Mar 2.

Links

Comment in:

Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4579-80.

Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory.

Campolongo P, Roozendaal B, Trezza V, Hauer D, Schelling G, McGaugh JL, Cuomo V.

Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy. patrizia.campolongo@uniroma1.it

Hippocampus. 2008;18(2):221-6.

Links

Prolonged glucocorticoid treatment decreases cannabinoid CB1 receptor density in the hippocampus.

Hill MN, Carrier EJ, Ho WS, Shi L, Patel S, Gorzalka BB, Hillard CJ.

Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada.

Neuropharmacology. 2008 Jan;54(1):206-12. Epub 2007 Jun 29.

Links

Regulation of hypothalamic endocannabinoid levels by neuropeptides and hormones involved in food intake and metabolism: insulin and melanocortins.

Matias I, Vergoni AV, Petrosino S, Ottani A, Pocai A, Bertolini A, Di Marzo V.

Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.

Psychoneuroendocrinology. 2007 Jul;32(6):636-50. Epub 2007 Jun 5.

Links

Early maternal deprivation and neonatal single administration with a cannabinoid agonist induce long-term sex-dependent psychoimmunoendocrine effects in adolescent rats.

Llorente R, Arranz L, Marco EM, Moreno E, Puerto M, Guaza C, De la Fuente M, Viveros MP.

Departamento de Fisiología (Fisiología Animal II), Facultad de Ciencias Biológicas, Universidad Complutense, Ciudad Universitaria, C/ Jose Antonio Novais, 2; 28040 Madrid, Spain.

Eur J Pharmacol. 2006 Aug 7;542(1-3):179-83. Epub 2006 Jun 2.

Links

The cannabinoid CB2 receptor inverse agonist JTE-907 suppresses spontaneous itch-associated responses of NC mice, a model of atopic dermatitis.

Maekawa T, Nojima H, Kuraishi Y, Aisaka K.

Department of Applied Pharmacology, Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.

J Neurosci. 2006 Jun 14;26(24):6643-50.

Links

Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release.

Malcher-Lopes R, Di S, Marcheselli VS, Weng FJ, Stuart CT, Bazan NG, Tasker JG.

Neuroscience Program, Tulane University, New Orleans, Louisiana 70118, USA. malcherlopes@gmail.com

J Neuroendocrinol. 2008 May;20 Suppl 1:35-8.

Links

The role of the endocannabinoid system in the regulation of hypothalamic-pituitary-adrenal axis activity.

Cota D.

Department of Psychiatry, Obesity Research Center, Genome Research Institute, University of Cincinnati, Cincinnati, OH 45237, USA. daniela.cota@uc.edu

The endocannabinoid system (ECS) is a recently identified neuromodulatory system, which is involved in several physiological processes and in disease. For example, the ECS not only represents the biological substrate of marijuana’s effects, but also is known to modulate several neuroendocrine axes, including the hypothalamic-pituitary-adrenal (HPA) axis. Although previous pharmacological studies using plant-derived or synthetic cannabinoids have implied a stimulating action on the HPA axis, more recent findings have led to the conclusion that an endogenous cannabinoid tone might exist, which is actually inhibiting the release of both adrenocorticotrophic hormone and glucocorticoids. Studies using mice lacking cannabinoid receptor CB(1) have demonstrated that presence and activity of these receptors is essential for the regulation of HPA axis activity. Interestingly, the effects of endocannabinoids on the HPA axis are consistent with their neuromodulatory action on brain neurotransmitter systems. Endocannabinoids have been found to mediate the nongenomic glucocorticoid-induced inhibition of the release of corticotrophin-releasing factor within the paraventricular nucleus of the hypothalamus. Altogether, these observations suggest that alterations of the endocannabinoid tone might be associated with the development of stress-related diseases, including anxiety, depression and obesity.

PMID: 18426497 [PubMed – indexed for MEDLINE]

+++++++++++++++++

Bari et al 2006

Mini Rev Med Chem. 2006 Mar;6(3):257-68.

Links

New insights into endocannabinoid degradation and its therapeutic potential.

Bari M, Battista N, Fezza F, Gasperi V, Maccarrone M.

Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

Endocannabinoids are amides,

….esters and ethers of long chain polyunsaturated fatty acids,

…..which act as new lipidic mediators.

Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of (-)-Delta9-tetrahydrocannabinol (THC), the active principle of Cannabis sativa preparations like hashish and marijuana.

The activity of AEA and 2-AG at their receptors is limited by cellular uptake through an anandamide membrane transporter (AMT),

………followed by intracellular degradation.

A fatty acid amide hydrolase (FAAH) is the main AEA hydrolase, whereas a monoacylglycerol lipase (MAGL) is critical in degrading 2-AG.

……….Here, we will review growing evidence that

…..demonstrates that these hydrolases are pivotal regulators of the endogenous levels of AEA and 2-AG in vivo, overall suggesting that specific inhibitors of AMT, FAAH or MAGL may serve as attractive therapeutic targets for the treatment of human disorders.

Recently, the N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD), which synthesizes AEA from N-arachidonoylphosphatidylethanolamine (NArPE), and the diacylglycerol lipase (DAGL), which generates 2-AG from diacylglycerol (DAG) substrates, have been characterized.

…………The

role of these synthetic routes in maintaining the endocannabinoid tone

in vivo will be discussed. Finally, the effects of inhibitors of endocannabinoid degradation in animal models of human disease will be reviewed, with an …..emphasis on their ongoing applications in anxiety, cancer and neurodegenerative disorders.

++++++++++++++++

Holter et al 2005

Eur J Pharmacol. 2005 Mar 7;510(1-2):69-74.

Links

Cannabinoid CB1 receptor is dispensable for memory extinction in an appetitively-motivated learning task.

Hölter SM, Kallnik M, Wurst W, Marsicano G, Lutz B, Wotjak CT.

Max-Planck-Institut für Psychiatrie, AG Neuronale Plastizität/Mausverhalten, Kraepelinstr. 2, D-80804 München, Germany.

The interaction of the cannabinoid CB1 receptor

……with its endogenous ligands

……plays an essential role in extinction of aversive memories (Marsicano, G., et al., 2002)

The present study tested the generality of this observation in respect to positively-reinforced memories. [I think Niyuhire et al 2007 states that food reward is different than aversive?]

To this end, male cannabinoid CB1 receptor deficient mice (CB1R-/-) and their wild-type littermate controls (CB1R+/+) were trained in an appetitively-motivated operant conditioning task, in which food-deprived animals received a food reward on nose-poking into an illuminated hole. During training, CB1R-/-

…..turned out to be less motivated to participate in the task.

…..After further restriction of daily food consumption, however, CB1R-/- reached the same level of performance as CB1R+/+ as far as number of correct responses and errors of omission are concerned.

…..The accuracy of performance served as a measure for the memory of the light-reward association and was stable at similarly high levels over a retention period of 9 days without additional training (97.6+/-0.5% vs. 97.0+/-0.9% correct responses).

……….During subsequent extinction training, the positive reinforcement was omitted.

As a consequence, both CB1R-/- and CB1R+/+ showed a similar decline in accuracy of performance and total number of correct responses, accompanied by an increase in errors of omission. These data demonstrate that the cannabinoid

………CB1 receptor is not essential for extinction of the stimulus-response association in an appetitively-motivated learning task.

[I think Niyuhire et al 2007 states that food reward is different than aversive? And probably influences the finding in this study as this might be true ONLY regarding appetite and food motivation.]

see also:

Pharmacol Biochem Behav. 2005 Jun;81(2):263-84.

Links

Endocannabinoid signaling system and brain reward: emphasis on dopamine.

Gardner EL.

Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Building C-Room 393, Baltimore, MD 21224, USA. egardner@intra.nida.nih.gov

++++++++++++++++++

Marsicano et al 2002

Nature. 2002 Aug 1;418(6897):530-4.

Links

Comment in:

Nature. 2002 Aug 1;418(6897):488-9.

The endogenous cannabinoid system controls extinction of aversive memories.

Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgänsberger W, Di Marzo V, Lutz B.

Molecular Genetics of Behaviour, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany.

Molecular genetics

Acquisition and storage of aversive memories is one of the basic principles of central nervous systems throughout the animal kingdom.

In the absence of reinforcement, the resulting behavioural response will gradually diminish to be finally extinct.

Despite the importance of extinction, its cellular mechanisms are largely unknown.

The cannabinoid receptor 1 (CB1) and endocannabinoids

……are present in memory-related brain areas

….and modulate memory.

Here we show that the endogenous cannabinoid system

has a central function in extinction of aversive memories.

CB1-deficient mice showed

…..strongly impaired short-term and long-term extinction in auditory fear-conditioning tests,

……with unaffected memory acquisition and consolidation.

Treatment of wild-type mice with the CB1 antagonist SR141716A mimicked the phenotype of CB1-deficient mice, revealing that

CB1 is required at the

moment of memory extinction.

Consistently, tone presentation during extinction trials resulted in

elevated levels of endocannabinoids

in the basolateral amygdala complex,

a region known

to control extinction of aversive memories.

in the

basolateral amygdala,

endocannabinoids and CB1

were crucially involved in long-term depression of GABA (gamma-aminobutyric acid)-mediated inhibitory currents.

We propose that endocannabinoids facilitate extinction

of aversive memories

through their selective inhibitory effects

on local inhibitory networks in the amygdala.

Linda note:  So they inhibit inhibition??  This is central to PTSD and problems with fear extinction.  If the body has a wisdom regarding the retention of fear, and will not let it extinguish after traumatic experiences, this is HOW that happens – and where.

What does this change for me, the knowing of the kernel within the seed within the shell?  Is this where the beta-blockers work, then?  And what is this feeling I am having, this almost tender feeling for the creation of our species, that makes a sperm fertile and helps it find its egg and protects that union once it has happened and directs the 2-cell to exactly where it is supposed to implant itself on the uterine wall?  That same system, the one that preserves or prevents or destroys the very beginnings of life holds onto or lets go of memories of terror.  How can I not believe that there is wisdom in this system, this wise, wise system that governs and signals so much of what we need to be here in the first place?  How can one not stand in awe at the gateway to life, fertilization and fear memory included equally among the jewels?  How can I not be astonished?  And how can I condemn the wisdom of one and condemn the wisdom of the other?

I feel that I went hunting for this treasure, and now that I’ve found this gem, I don’t know what to do with it, what it means, what it’s worth.  I know that it keeps the most excellent company.  This is no shoddy, no slap dash, no haphazard system we are dealing with here.  Or rather, the operation that is dealing with us.  The magic kiss of life.  “If something scares you that badly, it’s worth not forgetting.”  Could it all be this simple?  This clear?  This true?  This fundamental, this essential (as in the essence of life), and this necessary?

I think in some ways everything I have been studying and learning up to now has been about the WHAT that happens to us.  This part is about the how and where – and perhaps the why in terms of the physiological responses within the body.  If the endocannabinoid system is about the most fundamental signaling having to do with the conception of life —–?

And might it be true that it is within these junctures that some genetic combination is able to form the constitution of those who are more sensitive, and thus more “anxious” compared to those who are less anxious and less sensitive?  That these variations near the extremes evolved for a purpose?  That perhaps my biggest wish for what I could communicate in this book is to help people achieve a sense of respect and appreciation for the variances that exist in the human species, that give us a spectrum so that we are not all alike.  There has to be two ends to have a complete rainbow – unless one realizes that the other half of a rainbow is really under ground.  I think somebody told me that one time.  My memory seems to be that that person was so convincing I believed them when they told me that. ( Like mother with her cross on the screen door.)

I think it is a good thing if we can introduce into our awareness a sense of marvel at the amazing wisdom of our bodies.  If we can begin to understand the super highways within our bodies that carry messages of all kinds into every nook and cranny of who we are, that determine how we continually adjust to all the necessities of the world we live in.

And perhaps through my studies I can discover why it is I no longer ever feel a sense of safety, security or peace.  I used to have times when I was younger when I could walk within those rays of light.  But now the anxiety – I suppose registering in my hyperactive amygdala – keep me always in a state of readiness for something else – other than the peaceful.  Is this the fate of those of us who are super sensitive and have such incredible histories of maltreatment and abuse?  Has it always only been some cognitive construction of being in the right place at the right time that allowed me segments of my life where I did not feel this dis-ease that is really an uneasiness that is chronic, has been a part of who I am since terror, pain and abuse was programmed into my body and therefore my brain.

This system is where I suspect our genetics determine what we care about and to what degree.  What we are sensitive and what we are not.  What we react to, how we react, and it is involved in the intensity of our response – in the amygdala, and from there, in the rest of our body.  It determines the degree of our sensitivities and our tolerances for input from our environment, and from our body’s signals.

If we could watch traffic in a large city moving without seeing the central, or causative mechanisms that determine the organized flow, and we could not see the top lights – we would not know where the signaling for the orderly flow occurs.  Of course all drivers are participating in the “rules” of traffic movement or there would be mayhem.  It might be that this system is key and central to the signaling processes that occur throughout our bodies.

As long as the human race does not know something, if we are ignorant of something, then we have a mystery.  When we learn more, mystery solved, on to the next one.  I wonder if this area in our system-signaling is one of those mystery areas that once understood, will shed light on much else that troubles us.  Is this where dissociation begins?  If enough of these fear conditions pile up and are not continuously connected to one another, wouldn’t there be gaping “holes” in between in our memory, our emotional autobiographical experience of who we are?  Does this system signal our conscious awareness of who we are – starting with where we are?

Our continual learnings also enable us to expand and clarify our categories of thinking about our bodies and about our reactionary patterns to life.  Some people are more immune that others to disastrous occurrences – and it might be helpful to begin to think about our reactions in immune system terms – to put this research about “mental illness” in the framework of immunity or lack of.

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WORKING MEMORY

Varvel et al 2006

J Pharmacol Exp Ther. 2006 Apr;317(1):251-7. Epub 2005 Dec 13.

Links

Fatty acid amide hydrolase (-/-) mice exhibit an increased sensitivity to the disruptive effects of anandamide or oleamide in a working memory water maze task.

Varvel SA, Cravatt BF, Engram AE, Lichtman AH.

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, 23298-0613, USA

Although recent evidence suggests that fatty acid amide hydrolase (FAAH) may represent a potential therapeutic target, few published studies have investigated FAAH or its fatty acid amide substrates (FAAs) in animal models of learning and memory.

Therefore, our primary goal was to determine whether

….FAAH (-/-) mice, which possess elevated levels of anandamide and other FAAs,

…..would display altered performance in four Morris water maze tasks

…… FAAH (-/-) mice failed to exhibit deficits in any task; in fact, they initially acquired the working memory task more rapidly than FAAH (+/+) mice.

………The second goal of this study was to investigate whether the FAAH inhibitor OL-135 (1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane), anandamide, other FAAs, and methanandamide would affect working memory in both genotypes.

……….FAAH (-/-), but not (+/+), mice displayed working memory impairments following exogenous administration of anandamide (ED(50) = 6 mg/kg) or oleamide (50 mg/kg).

………However, the central cannabinoid receptor (CB(1)) receptor antagonist SR141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl]

………..only blocked the disruptive effects of anandamide.

Methanandamide, which is not metabolized by FAAH, disrupted working memory performance in both genotypes (ED(50) = 10 mg/kg), suggesting that CB(1) receptor signaling is unaltered by FAAH deletion.

……….In contrast, OL-135 and other FAAs failed to affect working memory in either genotype. These results suggest that

……..FAAH deletion does not impair spatial learning but may enhance acquisition under certain conditions.

………..More generally, FAAH may represent a novel therapeutic target that circumvents the undesirable cognitive side effects commonly associated with direct-acting cannabinoid agonists.

++++

See also:

Psychopharmacology (Berl). 2005 Jun;179(4):863-72. Epub 2004 Dec 24.

Links

Disruption of CB(1) receptor signaling impairs extinction of spatial memory in mice.

Varvel SA, Anum EA, Lichtman AH.

Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298-0613, USA.

J Neurosci. 2007 Feb 7;27(6):1325-33.

Links

Retrograde regulation of GABA transmission by the tonic release of oxytocin and endocannabinoids governs postsynaptic firing.

Oliet SH, Baimoukhametova DV, Piet R, Bains JS.

Institut National de la Santé et de la Recherche Médicale, Unité 862, Université Victor Segalen Bordeaux 2, Bordeaux 33077, France.

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Hill et al 2005

Eur J Pharmacol. 2005 Dec 28;528(1-3):99-102. Epub 2005 Dec 1.

Links

Chronic corticosterone treatment increases the endocannabinoid 2-arachidonylglycerol in the rat amygdala.

Hill MN, Ho WS, Meier SE, Gorzalka BB, Hillard CJ.

Department of Psychology, University of British Columbia, Vancouver, B.C. Canada V6T1Z4.

This research was designed to examine the effect of three weeks of administration of corticosterone (20 mg/kg) on endocannabinoid content and cannabinoid CB1 receptor binding in the amygdala. It was found that the endocannabinoid 2-arachidonylglycerol was significantly increased in the amygdala following chronic corticosterone treatment. However, there was no change in either the maximal binding (Bmax) or binding affinity (KD) of [3H]-CP 55,940 to the CB1 receptor in the amygdala.

Given the role of amygdalar endocannabinoids

in the regulation of emotionality,

this suggests that the ability of glucocorticoids

to influence affective behavior may involve

interactions with regulation of endocannabinoid content.

++++++++++++++++++

Patel et al 2005

Eur J Neurosci. 2005 Feb;21(4):1057-69.

Links

Inhibition of restraint stress-induced neural and behavioural activation by endogenous cannabinoid signalling.

Patel S, Roelke CT, Rademacher DJ, Hillard CJ.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

[GIVING UP OR FIGHTING BACK]

The role of endocannabinoid (eCB) signaling in restraint stress-induced neuronal activation was studied. Male mice exposed to 30 min of restraint exhibit increased Fos protein within prefrontal cortex (PFC), lateral septum (LS), nucleus accumbens (Acb) and medial amygdala. ….. These data suggest that

eCB activation of CB(1) receptors opposes the behavioural and neuronal responses to aversive stimuli.

Because repeated homotypic stress increased both limbic 2-AG and resulted in a greater effect of SR141716 on limbic Fos expression, we hypothesize that

increased CB(1) receptor activity contributes to the expression of habituation to homotypic stress

++++

See also:

Endocrinology. 2004 Dec;145(12):5431-8. Epub 2004 Aug 26.

Links

Comment in:

Endocrinology. 2004 Dec;145(12):5429-30.

Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis.

Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.

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A pubmed database search for “hypothalamus cannabinoid” brings up 360 articles.

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Berczi et al 1996

Baillieres Clin Rheumatol. 1996 May;10(2):227-57.

Links

The immune effects of neuropeptides.

Berczi I, Chalmers IM, Nagy E, Warrington RJ.

Department of Immunology, University of Manitoba, Winnipeg, Canada.

Current evidence [1996] indicates that the neuroendocrine system is the highest regulator of immune/inflammatory reactions. So how could it be a different system?

Prolactin and growth hormone

….stimulate the production of leukocytes,

……including lymphocytes,

…..and maintain immunocompetence.

The hypothalamus-pituitary-adrenal [HPA] axis

…..constitutes the most powerful circuit

……regulating the immune system.

The neuropeptides constituting this axis,

namely corticotrophin releasing factor [CRH] ,

adrenocorticotrophic hormone,

alpha-melanocyte stimulating hormone,

and beta-endorphin

are powerful immunoregulators,

which have a direct regulatory effect on lymphoid cells,

………..regulating immune reactions by the stimulation of immunoregulatory hormones (glucocorticoids)

……….and also by acting on the central nervous system which in turn generates immunoregulatory nerve impulses.

………Peptidergic nerves are major regulators of the inflammatory response.

……….Substance P and calcitonin gene-related peptide are pro-inflammatory mediators and

………somatostatin is anti-inflammatory.

The neuroendocrine regulation of the inflammatory response is of major significance from the point of view of immune homeostasis.

……….Malfunction of this circuit leads to disease

………and often is life-threatening.  And leads to what we call “psychopathologies” – same THING, same PROCESS

The immune system

emits signals

towards the neuroendocrine system

by cytokine mediators which reach significant blood levels (cytokine-hormones)

…..during systemic immune/inflammatory reactions.

…. Interleukin-1, -6, and TNF-alpha are the major cytokine hormones mediating the acute phase response.

……These cytokines induce profound neuroendocrine and metabolic changes by interacting with the central nervous system and with many other organs and tissues in the body.

Corticotrophin releasing factor [CRF] functions under these conditions as a major co-ordinator of the response

……and is responsible for activating the ACTH-adrenal axis

…..for regulating fever and for other CNS effects

….leading to a sympathetic outflow.

Increased ACTH secretion leads to glucocorticoid production.

….alpha-melanocyte stimulating hormone functions under these conditions as a cytokine antagonist and an anti-pyretic hormone.

…..The sympathetic outflow, in conjunction with increased adrenal activity. leads to the elevation of catecholamines in the bloodstream and in tissues.

Current evidence suggests that neuroimmune mechanisms are essential in normal physiology, such as tissue turnover, involution, atrophy, intestinal function, and reproduction.

….. Host defense against infection, trauma and shock

….relies heavily on the neuroimmunoregulatory network.

Including our response to “emotional” trauma and shock!

Moreover, abnormalities of neuroimmunoregulation contribute to the aetiology of autoimmune disease, chronic inflammatory disease, immunodeficiency, allergy, and asthma. Finally,

neuroimmune mechanisms play an important role in regeneration and healing.

Including regeneration and healing from so-called “psychopathologies”

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Vlachou, Nomikos & Panagis 2003

Behav Brain Res. 2003 May 15;141(2):215-22.

Links

WIN 55,212-2 decreases the reinforcing actions of cocaine through CB1 cannabinoid receptor stimulation.

Vlachou S, Nomikos GG, Panagis G.

Division of Biopsychology, Laboratory of Neurosciences and Behavior, Department of Psychology, School of Social Sciences, University of Crete, 74100 Rethymnon, Crete, Greece.

CB(1) cannabinoid receptor agonists show

…..a different profile compared to other drugs of abuse on the basis of experimental data that reveal their reinforcing properties.

Thus, there are controversial data in the literature concerning the ability of CB(1) receptor agonists to reinforce behavioral responses in experimental animals, i.e. to lower self-stimulation thresholds, and to support self-administration or conditioned place preference. T

he aim of the present study was to examine the effects of WIN 55,212-2, a potent CB(1) receptor agonist (graded doses 0.1, 0.3, 1 mg/kg, i.p.), on the rewarding efficacy of

lateral hypothalamic self-stimulation

and on the systemic cocaine-induced potentiation of brain-stimulation reward.

…….WIN 55,212-2 did not affect lateral hypothalamic self-stimulation thresholds both in drug naive rats and in rats pretreated with the drug,

…….whereas it produced a significant, dose-dependent decrease in the maximal rate of responding, i.e. in the performance of the animals. Cocaine (5.0 mg/kg, i.p.) produced a significant reduction in self-stimulation threshold, without altering maximal rates of responding. Importantly, WIN 55,212-2 attenuated the effect of cocaine at the two higher doses tested. The effects of the CB(1) receptor agonist were reversed by pretreatment with the selective CB(1) receptor antagonist SR 141716A (0.02 mg/kg, i.p.) that did not by itself affect cocaine’s action.

These results indicate

….that acute stimulation of CB(1) receptors per se does not affect baseline self-stimulation, but

…..reduces the reinforcing effects induced by cocaine.

Taken together these findings suggest that

….cannabinoids may interfere with brain-reward systems responsible for the expression of acute reinforcing properties of drugs of abuse, such as cocaine,

…….and provide evidence that the cannabinoid system could be an interesting drug discovery and development target for the treatment of drug addiction.

Reinforcing being different from reward?  Perhaps reinforcing is sort of like forming a pattern, that by itself is not about reward, perhaps is about habit?

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Onaivi et al 2006

Abstract – Department of Biology, William Paterson University, Wayne, NJ 07470, USA. Onaivie@wpunj.edu

Two well-characterized cannabinoid receptors (CBrs), CB1 and CB2, mediate the effects of cannabinoids and marijuana use, with functional evidence for other CBrs. CB1 receptors are expressed primarily in brain and peripheral tissues. For over a decade several laboratories were unable to detect CB2 receptors in brain and were known to be intensely expressed in peripheral and immune tissues and have traditionally been referred to as peripheral CB2 CBrs. We have reported the discovery and functional presence of CB2 cannabinoid receptors in mammalian brain that may be involved in depression and drug abuse and this was supported by reports of identification of neuronal CB2 receptors that are involved in emesis.

We used RT-PCR, immunoblotting, hippocampal cultures, immunohistochemistry, transmission electron microscopy, and stereotaxic techniques with behavioral assays to determine the functional expression of CB2 CBrs in rat brain and mice brain exposed to chronic mild stress (CMS) or those treated with abused drugs. RT-PCR analyses supported the expression of brain CB2 receptor transcripts at levels much lower than those of CB1 receptors. In situ hybridization revealed CB2 mRNA in cerebellar neurons of wild-type but not of CB2 knockout mice. Abundant CB2 receptor immunoreactivity (iCB2) in neuronal and glial processes was detected in brain and CB2 expression was detected in neuron-specific enolase (NSE) positive hippocampal cell cultures. The effect of direct CB2 antisense oligonucleotide injection into the brain and treatment with JWH015 in motor function and plus-maze tests also demonstrated the functional presence of CB2 cannabinoid receptors in the central nervous system (CNS).

Thus, contrary to the prevailing view that CB2 CBrs are restricted to peripheral tissues and predominantly in immune cells, we demonstrated that CB2 CBrs and their gene transcripts are widely distributed in the brain.

This multifocal expression of CB2 immunoreactivity in brain suggests that CB2 receptors may play broader roles in the brain than previously anticipated and may be exploited as new targets in the treatment of depression and substance abuse.

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Postsynaptic localization of CB2 cannabinoid receptors in the rat hippocampus.

Brusco A, Tagliaferro P, Saez T, Onaivi ES.

Synapse. 2008 Dec;62(12):944-9.

PMID: 18798269 [PubMed – indexed for MEDLINE]

Related Articles

Ultrastructural localization of neuronal brain CB2 cannabinoid receptors.

Brusco A, Tagliaferro PA, Saez T, Onaivi ES.

Ann N Y Acad Sci. 2008 Oct;1139:450-7.

PMID: 18991892 [PubMed – indexed for MEDLINE]

Related Articles

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Sugiura et al 2000

Abstract – Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Tsukui-gun, Kanagawa 199-0195, Japan.

These results strongly suggest that the CB2 receptor

is originally a 2-arachidonoylglycerol receptor,

and 2-arachidonoylglycerol is the intrinsic natural ligand for the CB2 receptor that is

abundant in the immune system.

++++

Kishimoto et al 2004

Abstract – Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195

2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). Previously, we provided evidence

that 2-arachidonoylglycerol,

but not anandamide (N-arachidonoylethanolamine), i

s the true natural ligand for the cannabinoid receptors.

In the present study, we examined in detail the effects of 2-arachidonoylglycerol on the production of chemokines in human promyelocytic leukemia HL-60 cells. We found that 2-arachidonoylglycerol induced a marked acceleration in the production of interleukin 8. The effect of 2-arachidonoylglycerol was blocked by treatment of the cells with SR144528, a cannabinoid CB2 receptor antagonist, indicating that the effect of 2-arachidonoylglycerol is mediated through the CB2 receptor. Augmented production of interleukin 8 was also observed with CP55940, a synthetic cannabinoid, and an ether-linked analog of 2-arachidonoylglycerol. On the other hand, neither anandamide nor the free arachidonic acid induced the enhanced production of interleukin 8. A similar effect of 2-arachidonoylglycerol was observed in the case of the production of macrophage-chemotactic protein-1. The accelerated production of interleukin 8 by 2-arachidonoylglycerol was observed not only in undifferentiated HL-60 cells, but also in HL-60 cells differentiated into macrophage-like cells. Noticeably, 2-arachidonoylglycerol and lipopolysaccharide acted synergistically to induce the dramatically augmented production of interleukin 8.

These results strongly suggest that the CB2 receptor and its physiological ligand, i.e., 2-arachidonoylglycerol,

play important regulatory roles such as stimulation of the production of chemokines in inflammatory cells and immune-competent cells.

Detailed studies on the cannabinoid receptor system are thus essential to gain a better understanding of the precise regulatory mechanisms of inflammatory reactions and immune responses.

+++++++++++

Sugiura et al 2000

J Biol Chem. 2000 Jan 7;275(1):605-12.

Links

Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells.

Sugiura T, Kondo S, Kishimoto S, Miyashita T, Nakane S, Kodaka T, Suhara Y, Takayama H, Waku K.

Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Tsukui-gun, Kanagawa 199-0195, Japan.

These results strongly suggest that the CB2 receptor

is originally a 2-arachidonoylglycerol receptor,

and 2-arachidonoylglycerol is the intrinsic natural ligand for the CB2 receptor that is

abundant in the immune system.

++++++++++++++++++++++++++++++

Kishimoto et al 2005

J Biochem. 2005 Feb;137(2):217-23.

Links

Endogenous cannabinoid receptor ligand induces the migration of human natural killer cells.

Kishimoto S, Muramatsu M, Gokoh M, Oka S, Waku K, Sugiura T.

Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195.

2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). Evidence is gradually accumulating which shows that 2-arachidonoylglycerol plays important physiological roles in several mammalian tissues and cells, yet the details remain ambiguous. In this study, ….. It is conceivable that

the endogenous ligand for the cannabinoid receptor,

that is, 2-arachidonoylglycerol,

affects natural killer cell functions such as migration, t

hereby contributing to the host-defense mechanism

against infectious viruses and tumor cells.

++++++++++++++++++++++++++

Kofalvi et al 2005

J Neurosci. 2005 Mar 16;25(11):2874-84.

Links

Involvement of cannabinoid receptors in the regulation of neurotransmitter release in the rodent striatum: a combined immunochemical and pharmacological analysis.

Köfalvi A, Rodrigues RJ, Ledent C, Mackie K, Vizi ES, Cunha RA, Sperlágh B.

Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1450, Hungary.

Despite the profound effect of cannabinoids on motor function, and their therapeutic potential in Parkinson’s and Huntington’s diseases, the cellular and subcellular distributions of striatal CB1 receptors are not well defined. Here, we show that CB1 receptors are primarily located on GABAergic (vesicular GABA transporter-positive) and glutamatergic [vesicular glutamate transporter-1 (VGLUT-1)- and VGLUT-2-positive] striatal nerve terminals and are present in the presynaptic active zone, in the postsynaptic density, as well as in the extrasynaptic membrane. ..

Cannabinoids modulated glutamate release via both CB1 and non-CB1 mechanisms. ….. indicating the involvement of non-CB1,CB1-like receptors. In contrast, cannabinoids did not modulate [3H]dopamine release or [3H]dopamine and [3H]GABA uptake.

Our results indicate distinct modulation of striatal GABAergic and glutamatergic transmission by cannabinoids and will facilitate the understanding of the role and importance of the cannabinoid system in normal and pathological motor function.

++++++++++++++++++++++++++++++

Battista et al 2006

Ital J Biochem. 2006 Sep-Dec;55(3-4):283-9.

Links

The endocannabinoid system in neurodegeneration.

Battista N, Fezza F, Finazzi-Agrò A, Maccarrone M.

Department of Biomedical Sciences, University of Teramo, Teramo, Italy

Endocannabinoids are bioactive lipids,

….that comprise amides, esters and ethers of long chain polyunsaturated fatty acids.

….role of the endocannabinoid pathway in neurodegenerative disorders, like Parkinson’s disease, Huntington’s disease, and multiple sclerosis.

++++++++++++++++++++++++++++++

Cabranes et al 2005

Neurobiol Dis. 2005 Nov;20(2):207-17.

Links

Decreased endocannabinoid levels in the brain and beneficial effects of agents activating cannabinoid and/or vanilloid receptors in a rat model of multiple sclerosis.

Cabranes A, Venderova K, de Lago E, Fezza F, Sánchez A, Mestre L, Valenti M, García-Merino A, Ramos JA, Di Marzo V, Fernández-Ruiz J.

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.

.

Recent studies have addressed the changes in endocannabinoid ligands and receptors that occur in multiple sclerosis, as a way to explain the efficacy of cannabinoid compounds to alleviate spasticity, pain, tremor, and other signs of this autoimmune disease. ….. In summary, our data suggest that reduction of endocannabinoid signaling is associated with the development of EAE in rats. We have also proved that the reduction of CB1 receptors observed in these rats is corrected following treatment with a compound used in EAE such as rolipram. In addition, the direct or indirect activation of vanilloid or cannabinoid receptors may reduce the neurological impairment experienced by EAE rats, although the efficacy of the different compounds examined seems to be determined by their particular pharmacodynamic and pharmacokinetic characteristics.

++++++++++++++++++++++++++++++++

Mini Rev Med Chem. 2006 Mar;6(3):257-68.

Links

New insights into endocannabinoid degradation and its therapeutic potential.

Bari M, Battista N, Fezza F, Gasperi V, Maccarrone M.

Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

Curr Neurovasc Res. 2004 Apr;1(2):129-40.

Links

Endocannabinoids and their involvement in the neurovascular system.

Battista N, Fezza F, Maccarrone M.

Department of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, I-64100 Teramo, Italy

++++++++++++++++++++++++++++++

Maccarrone, Battista & Centonze 2007

Prog Neurobiol. 2007 Apr;81(5-6):349-79. Epub 2007 Feb 2.

Links

The endocannabinoid pathway in Huntington’s disease: a comparison with other neurodegenerative diseases.

Maccarrone M, Battista N, Centonze D.

Department of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, 64100 Teramo, Italy. mmaccarrone@unite.it

Endocannabinoids are endogenous agonists of cannabinoid receptors, and …..comprise amides, esters and ethers of long chain polyunsaturated fatty acids.

Anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol are the best-studied members of this class of lipid mediators,

…and it is now widely accepted that their in vivo concentration and biological activity are largely dependent on a “metabolic control.”

Therefore, the proteins that synthesize, transport and degrade endocannabinoids, and that together with the target receptors form the so-called “endocannabinoid system,” are the focus of intense research.

This new system will be presented in this review, in order to put in a better perspective the impact of its modulation on Huntington’s disease.

In particular, the effect of agonists/antagonists of endocannabinoid receptors, or of inhibitors of endocannabinoid metabolism, will be discussed in the context of onset and progression of Huntington’s disease, and will be compared with other neurodegenerative diseases like Parkinson’s disease, Alzheimer’s disease, and amyotropic lateral sclerosis. Also the plastic changes of endocannabinoids in multiple sclerosis will be reviewed, as

a paradigm of their impact in neuroinflammatory disorders.

+++++++++++++++++++++++

Breivogel & Childers 1998

Neurobiol Dis. 1998 Dec;5(6 Pt B):417-31.

Links

The functional neuroanatomy of brain cannabinoid receptors.

Breivogel CS, Childers SR.

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA

The effects of the primary psychoactive constituent of marijuana, delta 9-tetrahydrocannabinol, are mediated by cannabinoid receptors, CB1 and CB2.

The CB1 receptors display a unique central nervous system (CNS) distribution and are present in mammalian brain at higher levels than most other known G-protein-coupled receptors.

……The highest levels occur in several areas involved in motor control and hippocampus.

Cannabinoid effects on CNS activities, including

..movement, ….memory, ….nociception, ….endocrine regulation, ….thermoregulation, ….sensory perception, ….cognitive functions, and ….mood,

correlate with the regional distribution of cannabinoid receptors and their activation of specific G-protein-mediated signal transduction systems in various brain regions.

++++++++++++++++++++++++++++++

Pickel et al 2004

Neuroscience. 2004;127(1):101-12.

Links

Compartment-specific localization of cannabinoid 1 (CB1) and mu-opioid receptors in rat nucleus accumbens.

Pickel VM, Chan J, Kash TL, Rodríguez JJ, MacKie K.

Department of Neurology and Neuroscience, Cornell University Medical College, 411 East 69th Street, Room KB-410, New York, NY 10021, USA. vpickel@mail.med.cornell.edu

Interactions

between cannabinoid and opioid systems

have been implicated in reward and drug seeking behaviors

involving neuronal circuitry

in the nucleus accumbens (Acb) shell and core.

To determine the relevant sites, we examined the electron microscopic localization of cannabinoid type-1 (CB1) receptors and mu-opioid receptors in each Acb compartment in rat brain. CB1 receptor immunogold labeling was seen on the plasma membrane and within the cytoplasm of neuronal and glial profiles throughout the Acb. These neuronal profiles included somata and dendrites as well as axon terminals, many of which formed excitatory-type, asymmetric synapses with notable perforations that are often associated with synaptic plasticity.

The number of CB1-labeled terminals within the neuropil of the Acb shell was significantly greater than in the core.

Mu-opioid receptors were also detected in axonal and dendritic profiles.

These dendrites were most prevalent in the Acb shell, where mu-receptors also were located in 21% of the dendritic profiles and 3% of the axon terminals containing CB1 receptors.

More of the CB1-labeled terminals contacted dendrites expressing mu-opioid receptors in the shell (19%) compared with the core (13%).

Conversely, of the synaptic mu-labeled terminals, 20% in the shell and 10% in the core contacted dendrites containing CB1 receptors.

These findings provide ultrastructural evidence

that cannabinoid-opioid interactions

are mediated by activation of CB1 and mu-opioid receptors

within the same or synaptically linked neurons

in the Acb shell and core.

They also suggest a particularly important role for presynaptic CB1 receptors in the reward circuit of the Acb shell.

See also:

Pickel et al 2006b

J Comp Neurol. 2006 Mar 20;495(3):299-313.

Links

Targeting dopamine D2 and cannabinoid-1 (CB1) receptors in rat nucleus accumbens.

Pickel VM, Chan J, Kearn CS, Mackie K.

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA. vpickel@mail.med.cornell.edu

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NEURON INFLAMATION – IMMUNE FUNCTION

Pazos et al 2005

Functional neuroanatomy of the endocannabinoid system.

Pazos MR, Núñez E, Benito C, Tolón RM, Romero J.

Pharmacol Biochem Behav. 2005 Jun;81(2):239-47. Review.

PMID: 15936805 [PubMed – indexed for MEDLINE]

Related Articles

See also:

A glial endogenous cannabinoid system is upregulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis.

Benito C, Kim WK, Chavarría I, Hillard CJ, Mackie K, Tolón RM, Williams K, Romero J.

J Neurosci. 2005 Mar 9;25(10):2530-6. Erratum in: J Neurosci. 2005 Mar 30;25(13):1 p following 3477. Kim, Wong-Ki [corrected to Kim, Woong-Ki];Williams, Ken [corrected to Williams, Kenneth].

PMID: 15758162 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

The endocannabinoid system: physiology and pharmacology.

Rodríguez de Fonseca F, Del Arco I, Bermudez-Silva FJ, Bilbao A, Cippitelli A, Navarro M.

Alcohol Alcohol. 2005 Jan-Feb;40(1):2-14. Epub 2004 Nov 18. Review.

PMID: 15550444 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

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Onaivi et al 2002

Prog Neurobiol. 2002 Apr;66(5):307-44.

Links

Endocannabinoids and cannabinoid receptor genetics.

Onaivi ES, Leonard CM, Ishiguro H, Zhang PW, Lin Z, Akinshola BE, Uhl GR.

Department of Biology, William Paterson University, 07470, Wayne, NJ, USA. eonaivi@intra.nida.nih.gov

This review presents the remarkable advances that have been achieved in marijuana (cannabinoid) research, with the discovery of specific receptors and the existence of naturally occurring cannabis-like substances in the human body and brain. The last decade has seen more rapid progress in marijuana research than any time in the thousands of years that marijuana has been used by humans, particularly in cannabinoid genomics.

…. Pursuing cannabinoid-related molecular, pharmacological and behavioral leads will add greatly to our understanding of endogenous brain neuromodulator systems, abused substances and potential therapeutics. This review of CB1 and CB2 Cnr genes in human and animal brain and their neurobiological effects provide a basis for many of these studies. Therefore, understanding the physiological cannabinoid control system in the human body and brain will contribute to elucidating this natural regulatory mechanism in health and disease.

See also:

Methods Mol Med. 2006;123:1-17.

Links

Molecular neurobiological methods in marijuana-cannabinoid research.

Uhl GR, Ishiguro H, Onaivi ES, Zhang PW, Akinshola BE, Lin Z, Hope B, Leonard CM, Liu QR.

Molecular Neurobiology Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.

Recent aggregation of evidence for the roles of endogenous agonist and receptor systems that are mimicked or activated by cannabanoid ligands has provided a focus for work that has elucidated details of some of the multiple physiological roles and pharmacological functions that these systems play in brain and peripheral tissues. This chapter reviews some of the approaches to improved elucidation of these systems, with special focus on the human genes that encode cannabanoid receptors and the variants in these receptors that appear likely to contribute to human addiction vulnerabilities.

+++++++++++++++++++++++++++++++

Neuropharmacology. 2004;47 Suppl 1:345-58.

Links

Cannabinoid physiology and pharmacology: 30 years of progress.

Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ.

Neuroscience of Drug Abuse Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA. ahowlett@wpo.nccu.edu

Delta9-Tetrahydrocannabinol from Cannabis sativa is mimicked by cannabimimetic analogs such as CP55940 and WIN55212-2, and antagonized by rimonabant and SR144528, through G-protein-coupled receptors, CB1 in the brain, and CB2 in the immune system. Eicosanoids anandamide and 2-arachidonoylglycerol are the “endocannabinoid” agonists for these receptors. CB1 receptors are abundant in basal ganglia, hippocampus and cerebellum…..

….Tolerance develops as neurons adjust both receptor number and cellular signal transduction to the chronic administration of cannabinoid drugs. Future therapeutic drug design can progress based upon our current understanding of the physiology and pharmacology of CB1, CB2 and related receptors. One very important role for CB1 antagonists will be in the treatment of craving in the disease of substance abuse.

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Fernandez-Ruiz et al 2008

Mol Cell Endocrinol. 2008 Apr 16;286(1-2 Suppl 1):S91-6. Epub 2008 Jan 17.

Links

Role of CB2 receptors in neuroprotective effects of cannabinoids.

Fernández-Ruiz J, Pazos MR, García-Arencibia M, Sagredo O, Ramos JA.

Department of Biochemistry and Molecular Biology, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Faculty of Medicine, Complutense University, 28040 Madrid, Spain. jjfr@med.ucm.es

CB2 receptors, the so-called peripheral cannabinoid receptor type, were first described in the immune system, but they have been recently identified in the brain in healthy conditions and, in particular, after several types of cytotoxic stimuli.

Specifically, CB2 receptors were identified in microglial cells, astrocytes and, to a lesser extent, in certain subpopulations of neurons. Given the lack of psychoactivity demonstrated by selective CB2 receptor agonists, this receptor becomes an interesting target for the treatment of neurological diseases, in particular, the case of certain neurodegenerative disorders in which induction/up-regulation of CB2 receptors has been already demonstrated. These disorders include Alzheimer’s disease, Huntington’s chorea, amyotrophic lateral sclerosis and others. Interestingly, in experimental models of these disorders, the activation of CB2 receptors has been related to a delayed progression of neurodegenerative events, in particular, those related to the toxic influence of microglial cells on neuronal homeostasis. The present article will review the evidence supporting that

CB2 receptors might represent a key element in the endogenous response against different types of cytotoxic events,

and that this receptor type may be a clinically promising target for the control of brain damage in neurodegenerative disorders.

++++

See also:

Cell Adh Migr. 2008 Oct;2(4):246-8. Epub 2008 Oct 5.

Links

Cannabinoid signaling system: does it play a function in cell proliferation and migration, neuritic elongation and guidance and synaptogenesis during brain ontogenesis?

Gómez M, Hernández M, Fernández-Ruiz J.

Departamento de Bioquímica y Biología Molecular and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.

Glia. 2008 Dec 29. [Epub ahead of print]

Links

Cannabinoid CB(2) receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington’s disease.

Sagredo O, González S, Aroyo I, Pazos MR, Benito C, Lastres-Becker I, Romero JP, Tolón RM, Mechoulam R, Brouillet E, Romero J, Fernández-Ruiz J.

Departamento de Bioquímica y Biología Molecular and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain.

Curr Pharm Des. 2008;14(23):2317-25.

Links

The endocannabinoid system in Huntington’s disease.

Pazos MR, Sagredo O, Fernández-Ruiz J.

Departamento de Bioquímica y Biología Molecular III and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.

Neuropharmacology. 2008 May;54(6):976-88. Epub 2008 Feb 16.

Links

CB1 receptor blockade reduces the anxiogenic-like response and ameliorates the neurochemical imbalances associated with alcohol withdrawal in rats.

Rubio M, Fernández-Ruiz J, de Miguel R, Maestro B, Michael Walker J, Ramos JA.

Departamento de Bioquímica y Biología Molecular and Centro de Investigación biomédica en Red sobre Enfermedades Neurodegenerativas, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.

J Histochem Cytochem. 2008 May;56(5):511-6. Epub 2008 Feb 18.

Links

Cannabinoid CB1 receptors are expressed by parietal cells of the human gastric mucosa.

Pazos MR, Tolón RM, Benito C, Rodríguez CF, Gorgojo JJ, Nevado M, Alvarez M, Arias F, Almodóvar F, Fernández MT, Lledó JL, González S, Fernández-Ruiz JJ, Romero J.

Laboratory of Research and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Fundación Hospital Alcorcón, Alcorcón, Madrid, Spain.

CNS Neurol Disord Drug Targets. 2007 Dec;6(6):377-87.

Links

Cannabinoids and neuroprotection in motor-related disorders.

de Lago E, Fernández-Ruiz J.

Departamento de Bioquímica y Biología Molecular and Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Complutense, 28040- Madrid, Spain. elagofem@med.ucm.es

Br J Pharmacol. 2001 Nov;134(6):1319-27.

Links

Effects of cannabinoids on adrenaline release from adrenal medullary cells.

Niederhoffer N, Hansen HH, Fernandez-Ruiz JJ, Szabo B.

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Freiburg i. Br., Germany. niederho@uni-freiburg.de

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McPartland, Norris & Kilpatrick 2007

Expert Opin Investig Drugs. 2006 Apr;15(4):351-65.

Links

Targeting the endocannabinoid system in treating brain disorders.

Bahr BA, Karanian DA, Makanji SS, Makriyannis A.

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA. Bahr@uconn.edu

Recent cannabinoid research has a primary focus on developing therapeutics against human diseases. Many studies on cannabinoids indicate important progress for protection against several neurodegenerative disorders. Agonists of cannabinoid receptors activate signaling pathways in the brain that are linked to neuronal repair and cell maintenance, and endogenous ligands can also activate neuroprotective responses.

These endocannabinoids are bioactive fatty acid amides and esters that are synthesized in the brain and include arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol.

Endocannabinoids are released

in response to pathogenic events,

thus representing a potential compensatory repair mechanism.

Enhancing this on-demand action of endocannabinoids is a strategy with which to promote endogenous repair signaling. …..This review highlights recent studies implicating the endocannabinoid system in neuroprotection against different disorders of the CNS.

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Croxford 2003

CNS Drugs. 2003;17(3):179-202.

Links

Therapeutic potential of cannabinoids in CNS disease.

Croxford JL.

Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60610, USA. j-croxford@northwestern.edu

The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC),

….and endogenous cannabinoid ligands, such as anandamide,

….signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes.

Signaling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial.

Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson’s disease

by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons.

The inhibitory effect of cannabinoids on reactive oxygen species, glutamate

….and tumour necrosis factor suggests that they

…..may be potent neuroprotective agents.

Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety.

………These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of

………..nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits.

The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via

the endocannabinoid system

may also reduce adverse effects and increase the efficacy of cannabinoid treatment.

+++++++++++++++++++++++++++++

Palmer, Khanolkar & Makriyannis 2000

Curr Pharm Des. 2000 Sep;6(13):1381-97.

Links

Natural and synthetic endocannabinoids and their structure-activity relationships.

Palmer SL, Khanolkar AD, Makriyannis A.

Departments of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.

During the past several years, cannabinoid biology has witnessed marked advances that has propelled it to the forefront of biomedical research. These new developments have also provided an opportunity to examine the physiological and biochemical events underlying the use and abuse of cannabis as well as elucidating the biological role of the endogenous cannabinoid ligands (endocannabinoids). The biological targets for endocannabinoids include the cannabinoid receptors (CB1 and CB2), the enzyme anandamide amidohydrolase (AAH), and the

carrier protein referred to as the anandamide transporter (ANT).

The identification of arachidonylethanolamide (anandamide, AEA) as an endogenous cannabinoid has been an important development in cannabinoid research which has led to the identification of two proteins associated with cannabinoid physiology in addition to the CB1 and CB2 receptors.

These proteins are anandamide amidohydrolase (AAH), an enzyme responsible for the hydrolytic breakdown of anandamide and the anandamide transporter (ANT), a carrier protein involved in the transport of anandamide across the cell membrane.

Evidence obtained so far suggests that these two proteins, in combination, are responsible for the termination of the biological actions of anandamide. Also, the discovery of anandamide has revealed a novel class of more selective agents possessing somewhat different pharmacological properties than the cannabinoids.

See also:

Chem Phys Lipids. 2000 Nov;108(1-2):37-52.

Links

Molecular probes for the cannabinoid receptors.

Khanolkar AD, Palmer SL, Makriyannis A.

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA. atmaram@uconnvm.uconn.edu

++++++++++++++++++++++++++++++

Glaser, Kaczocha & Deutsch 2005b

Life Sci. 2005 Aug 19;77(14):1584-604.

Links

Anandamide transport: a critical review.

Glaser ST, Kaczocha M, Deutsch DG.

Medical Department, Brookhaven National Laboratory, Upton, New York 11973, United States.

Anandamide (AEA) uptake has been described over the last decade

… to occur by facilitated diffusion,

….but a protein has yet to be isolated.

In some cell types, it has recently been suggested that

…..AEA, an uncharged hydrophobic molecule,

……passively diffuses through the plasma membrane in a process that is not protein-mediated.

Furthermore, at long incubation times, antagonists to AEA receptors reduce AEA uptake. Another complicating factor in AEA transport studies is the nonspecific binding to plastic culture dishes.

…….The magnitude of this effect may exceed AEA uptake into cells.

…………. Likewise, AEA may be released from plastic culture dishes (without cells) in such a manner as to mimic efflux from cells.

Their targets are now being characterized with the possibility that a protein transporter for AEA may be characterized.

++++++++++++++++++++++++++++++

Navarrete & Araque 2008

Neuron. 2008 Mar 27;57(6):883-93.

Links

Endocannabinoids mediate neuron-astrocyte communication.

Navarrete M, Araque A.

Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid 28002, Spain.

involvement in the neuron-astrocyte communication

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Bindukumar et al 2008

Brain Res. 2008 Jan 29;1191:1-11. Epub 2007 Nov 1.

Links

Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes.

Bindukumar B, Mahajan SD, Reynolds JL, Hu Z, Sykes DE, Aalinkeel R, Schwartz SA.

Department of Medicine, Division of Allergy, Immunology, and Rheumatology, Buffalo General Hospital, University at Buffalo, State University of NY, Kaleida Health, 100 High Street, Buffalo, NY 14203, USA.

global molecular effects of cannabinoids on normal human astrocytes (NHA) using genomic and proteomic analyses.

expression of more than 20 translated protein gene products from NHA was differentially dysregulated by treatment with Delta(9)-THC

Kreutz et al 2008

Glia. 2009 Feb;57(3):286-94.

Links

2-Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal-cannabidiol-sensitive receptors on microglial cells.

Kreutz S, Koch M, Böttger C, Ghadban C, Korf HW, Dehghani F.

Dr. Senckenbergische Anatomie, Institut für Anatomie II, J. W. Goethe-Universität, Frankfurt am Main, Germany.

2-AG modulates migration and proliferation of microglial cells

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Endocannabinoid modulation of scratching response in an acute allergenic model: a new prospective neural therapeutic target for pruritus.

Schlosburg JE, Boger DL, Cravatt BF, Lichtman AH.

J Pharmacol Exp Ther. 2009 Apr;329(1):314-23. Epub 2009 Jan 23.

PMID: 19168707 [PubMed – indexed for MEDLINE]

Related Articles

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Accorsi-Mendonça et al 2008

Brain Res. 2008 Mar 20;1200:1-9. Epub 2008 Jan 16.

Links

Inhibition of spontaneous neurotransmission in the nucleus of solitary tract of the rat by the cannabinoid agonist WIN 55212-2 is not via CB1 or CB2 receptors.

Accorsi-Mendonça D, Almado CE, Dagostin AL, Machado BH, Leão RM.

Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes, 3900 14049-900 Ribeirão Preto, SP, Brazil

Cannabinoids have been shown to

modulate central autonomic regulation

and baroreflex control of blood pressure.

Both CB1 and CB2 cannabinoid receptors

have been described in the nucleus tractus solitarius (NTS),

which receives direct afferent projections of cardiovascular reflexes.

In the present study we evaluated the effects of WIN 55212-2 (WIN), a cannabinoid agonist, on fast neurotransmission in the NTS.

We conclude WIN inhibits the neurotransmission in the NTS of young rats via a receptor

distinct

from CB1 or CB2.

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J Neuroendocrinol. 2008 May;20 Suppl 1:139-46.

Links

CB1 receptor blockade and its impact on cardiometabolic risk factors: overview of the RIO programme with rimonabant.

Scheen AJ.

Division of Diabetes, Nutrition and Metabolic Disorders and Clinical Pharmacology Unit, CHU Sart Tilman, University of Liege, Liege, Belgium. andre.scheen@chu.ulg.ac.be

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Batkai et al 2004

Circulation. 2004 Oct 5;110(14):1996-2002. Epub 2004 Sep 27.

Links

Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension.

Bátkai S, Pacher P, Osei-Hyiaman D, Radaeva S, Liu J, Harvey-White J, Offertáler L, Mackie K, Rudd MA, Bukoski RD, Kunos G.

Laboratory of Physiologic Studies, National Institute on Alcohol Abuse & Alcoholism, National Institutes of Health, Bethesda, Md 20892-8115, USA

BACKGROUND: Endocannabinoids are novel lipid mediators with hypotensive and cardiodepressor activity. Here, we examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension.

…. endocannabinoids tonically suppress cardiac contractility in hypertension and that enhancing the CB1-mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension.

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Herradon, Martin & Lopez-Miranda 2007

Br J Pharmacol. 2007 Nov;152(5):699-708. Epub 2007 Aug 20.

Links

Characterization of the vasorelaxant mechanisms of the endocannabinoid anandamide in rat aorta.

Herradón E, Martín MI, López-Miranda V.

Area de Farmacología, Dpto. Ciencias de la Salud III, Facultad Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain.

BACKGROUND AND PURPOSE: Studies in isolated preparations of vascular tissue (mainly resistance vessels) provide evidence that anandamide exerts vasorelaxation. The aim of the present work was to further characterize the mechanisms involved in the vascular response induced by anandamide in a conduit vessel, rat aorta.

KEY RESULTS: Anandamide caused a significant concentration-dependent vasorelaxation in rat aorta.

CONCLUSIONS AND IMPLICATIONS: Our results demonstrate, for the first time, the involvement of the non-CB1/non-CB2 cannabinoid receptor

…..and an anandamide-arachidonic acid-COX-2 derived metabolite (which acts on EP4 receptors)

…..in the endothelial vasorelaxation caused by anandamide in rat aorta.

+++++++++++++++++++++++++

Hiley & Ford 2004

Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling.

Hiley CR, Ford WR.

Biol Rev Camb Philos Soc. 2004 Feb;79(1):187-205. Review.

PMID: 15005177 [PubMed – indexed for MEDLINE]

Related Articles

Cannabinoids include not only plant-derived compounds (of which delta9-tetrahydrocannabinol is the primary psychoactive ingredient of cannabis),

……but also synthetic agents

………and endogenous substances termed endocannabinoids which include anandamide (2-arachidonoylethanolamide) and 2-arachidonoylglycerol.

Cannabinoids act on specific, G-protein-coupled, receptors which are currently divided into two types, CB1 and CB2. Relatively selective agonists and antagonists for these receptors have been developed, although one agent (SR141716A) widely used as an antagonist at CB1 receptors has non-cannabinoid receptor-mediated effects at concentrations which are often used to define the presence of the CB1 receptor.

……..Both cannabinoid receptors are primarily coupled to Gi/o proteins and act to inhibit adenylyl cyclase. Stimulation of CB1 receptors also modulates the activity of K+ and Ca2+ channels and of protein kinase pathways including protein kinase B (Akt) which might mediate effects on

……..apoptosis.

………CB, receptors may activate the extracellular signal-regulated kinase cascade through ceramide signalling.

Cannabinoid actions on the cardiovascular system

…have been widely interpreted as being mediated by CB1 receptors although there are a growing number of observations, particularly in isolated heart and blood vessel preparations, that suggest that other cannabinoid receptors may exist.

Interestingly, the currently identified cannabinoid receptors appear to be related to a wider family of lipid receptor, those for the lysophospholipids, which are also linked to Gi/o protein signalling.

Anandamide also activates vanilloid VR1 receptors

…..on sensory nerves and
….releases the vasoactive peptide, calcitonin gene-related peptide (CGRP), which brings about vasodilatation through its action on CGRP receptors.

Current evidence suggests that endocannabinoids have important protective roles in pathophysiological conditions such as shock and myocardial infarction.

Therefore, their cardiovascular effects and the receptors mediating them are the subject of increasing investigative interest.

Anandamide reduces infarct size in rat isolated hearts subjected to ischaemia-reperfusion by a novel cannabinoid mechanism.

Underdown NJ, Hiley CR, Ford WR.

Br J Pharmacol. 2005 Nov;146(6):809-16.

PMID: 16158067 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Endocannabinoids as mediators in the heart: a potential target for therapy of remodelling after myocardial infarction?

Hiley CR, Ford WR.

Br J Pharmacol. 2003 Apr;138(7):1183-4.

PMID: 12711614 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Evidence of a novel site mediating anandamide-induced negative inotropic and coronary vasodilatator responses in rat isolated hearts.

Ford WR, Honan SA, White R, Hiley CR.

Br J Pharmacol. 2002 Mar;135(5):1191-8.

PMID: 11877326 [PubMed – indexed for MEDLINE]

Mechanisms of anandamide-induced vasorelaxation in rat isolated coronary arteries.

White R, Ho WS, Bottrill FE, Ford WR, Hiley CR.

Br J Pharmacol. 2001 Oct;134(4):921-9.

PMID: 11606334 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Endocannabinoid degradation, endotoxic shock and inflammation.

Maccarrone M, Bari M, Battista N, Finazzi-Agrò A.

Curr Drug Targets Inflamm Allergy. 2002 Mar;1(1):53-63. Review.

PMID: 14561206 [PubMed – indexed for MEDLINE]

Related Articles

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Williams et al 2008

J Physiol. 2008 Feb 1;586(3):835-45. Epub 2007 Dec 6.

Links

The group IV afferent neuron expresses multiple receptor alterations in cardiomyopathyic rats: evidence at the cannabinoid CB1 receptor.

Williams MA, Smith SA, O’Brien DE, Mitchell JH, Garry MG.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9174, USA.

The exercise pressor reflex (EPR) is an important neural mechanism that controls blood pressure and heart rate during static muscle contraction. ….. The data suggest that the responsiveness of CB(1) receptors on group IV afferent neurons is blunted in cardiomyopathy. Importantly, these data indicate that group IV primary afferent neurons express multiple receptor defects in cardiomyopathy that may contribute to the decreased CB(1) receptor sensitivity in this disease.

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J Physiol Pharmacol. 2008 Dec;59 Suppl 8:91-107.

Links

Role of endocannabinoids in cardiovascular shock.

Malinowska B, Lupinski S, Godlewski G, Baranowska U, Schlicker E.

Department of Experimental Physiology, Medical University of Bialystok, Bialystok, Poland. bmalin@umwb.edu.pl

Endocannabinoids (e.g. anandamide, 2-arachidonoylglycerol or virodhamine) regulate the function of the cardiovascular system mainly in the following way: 1) by acting via CB(1) receptors, 2) by activation of CB(2) receptors, and 3) by modifying the function of vanilloid TRPV1, serotonin 5-HT(3) and alpha(7)-subunit-containing nicotinic acetylcholine receptors. Endocannabinoids are implicated in the pathogenesis of hypertension and of hypotension associated with haemorrhagic, endotoxic, and cardiogenic shock, and with advanced liver cirrhosis. There is also evidence for their involvement in the control of atherosclerosis.

PMID: 19258666 [PubMed – indexed for MEDLINE

See also:

Orv Hetil. 2002 Jun 30;143(26):1563-8.

Links

[Cardiovascular effects of cannabinoids]

[Article in Hungarian]

Járai Z, Kúnos G.

Fóvárosi Onkormányzat Szent Imre Kórház, I. Belgyógyászati Osztály, Budapest.

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LIVER

Batkai et al 2007

Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1689-95. Epub 2007 Jun 8.

Links

Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats.

Bátkai S, Mukhopadhyay P, Harvey-White J, Kechrid R, Pacher P, Kunos G.

Section on Neuroendocrinology, Laboratory of Physiological Studies, NIAAA, National Institutes of Health, MSC 9413, Rm. 2N17, 5625 Fishers Lane, Bethesda, MD 20892-9413, USA. sbatkai@mail.nih.gov

Advanced liver cirrhosis is associated with hyperdynamic circulation consisting of systemic hypotension, decreased peripheral resistance, and cardiac dysfunction, termed cirrhotic cardiomyopathy. Previous studies have revealed the role of endocannabinoids and vascular CB(1) receptors in the development of generalized hypotension and mesenteric vasodilation in animal models of liver cirrhosis, and CB(1) receptors have also been implicated in the decreased beta-adrenergic responsiveness of isolated heart tissue from cirrhotic rats. Here we document the cardiac contractile dysfunction in vivo in liver cirrhosis and explore the role of the endocannabinoid system in its development.

……. tissue levels of the endocannabinoid anandamide increased 2.7-fold in the heart of cirrhotic compared with control rats, without any change in 2-arachidonoylglycerol levels, whereas, in the cirrhotic liver, both 2-arachidonoylglycerol (6-fold) and anandamide (3.5-fold) were markedly increased. CB(1)-receptor expression in the heart was unaffected by cirrhosis

….. Activation of cardiac CB(1) receptors by endogenous anandamide

….contributes to the reduced cardiac contractility in liver cirrhosis,

…….and CB(1)-receptor antagonists may be used to improve contractile function in cirrhotic cardiomyopathy and, possibly, in other forms of heart failure.

+++++++++++++++++++++++++

Br J Pharmacol. 2007 Nov;152(5):699-708. Epub 2007 Aug 20.

Links

Characterization of the vasorelaxant mechanisms of the endocannabinoid anandamide in rat aorta.

Herradón E, Martín MI, López-Miranda V.

Area de Farmacología, Dpto. Ciencias de la Salud III, Facultad Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain.

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SEPTIC SHOCK

++++

Godlewski, Malinowska & Schlicker 2004

Br J Pharmacol. 2004 Jun;142(4):701-8. Epub 2004 May 24.

Links

Presynaptic cannabinoid CB(1) receptors are involved in the inhibition of the neurogenic vasopressor response during septic shock in pithed rats.

Godlewski G, Malinowska B, Schlicker E.

Zaklad Fizjologii Doswiadczalnej, Akademia Medyczna w Bialymstoku, ul. Mickiewicza 2A, PL 15-089 Bialystok, Poland. ggodl@amb.edu.pl

1. Our study was undertaken to investigate whether bacterial endotoxin/lipopolysaccharide (LPS) affects the neurogenic vasopressor response in rats in vivo by presynaptic mechanisms and, if so, to characterize the type of presynaptic receptor(s) operating in the initial phase of septic shock. 2. In pithed and vagotomized rats treated with pancuronium, electrical stimulation (ES) (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sympathetic nerve fibers or intravenous bolus injection of noradrenaline (NA) (1-3 nmol x kg(-1)) increased the diastolic blood pressure (DBP) by about 30 mmHg. Administration of LPS (0.4 and 4 mg x kg(-1)) under continuous infusion of vasopressin inhibited the neurogenic vasopressor response by 25 and 50%, respectively. LPS did not affect the increase in DBP induced by exogenous NA. 3. The LPS-induced inhibition of the neurogenic vasopressor response was counteracted by the cannabinoid CB(1) receptor antagonist SR 141716A (0.1 micromol x kg(-1)), but not by the CB(2) receptor antagonist SR 144528 (3 micromol x kg(-1)), the vanilloid VR1 receptor antagonist capsazepine (1 micromol x kg(-1)) or the histamine H(3) receptor antagonist clobenpropit (0.1 micromol x kg(-1)). The four antagonists by themselves did not affect the increase in DBP induced by ES or by injection of NA in rats not exposed to LPS. 4. We conclude that

in the initial phase of septic shock,

the activation of presynaptic CB(1) receptors

by endogenously formed cannabinoids

contributes to the inhibition of the neurogenic vasopressor response.

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Hiley & Hoi 2007

Cardiovasc Drug Rev. 2007 Spring;25(1):46-60.

Links

Oleamide: a fatty acid amide signaling molecule in the cardiovascular system?

Hiley CR, Hoi PM.

Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK. crh1@cam.ac.uk

Oleamide (cis-9,10-octadecenoamide), a fatty acid primary amide discovered in the cerebrospinal fluid of sleep-deprived cats, has a variety of actions that give it potential as a signaling molecule, although these actions have not been extensively investigated in the cardiovascular system.

The synthetic pathway probably involves synthesis of oleoylglycine and then conversion to oleamide by peptidylglycine alpha-amidating monooxygenase (PAM); breakdown of oleamide is by fatty acid amide hydrolase (FAAH). Oleamide interacts with voltage-gated Na(+) channels and allosterically with GABA(A) and 5-HT(7) receptors as well as having cannabinoid-like actions.

…….The latter have been suggested to be due to potentiation of the effects of endocannabinoids such as anandamide by inhibiting FAAH-mediated hydrolysis.

………This might underlie an “entourage effect” whereby co-released endogenous nonagonist congeners of endocannabinoids protect the active molecule from hydrolysis by FAAH.

…………However, oleamide has direct agonist actions at CB(1) cannabinoid receptors and also activates the TRPV1 vanilloid receptor. Other actions include inhibition of gap-junctional communication, and this

might give oleamide a role in myocardial development.

Many of these actions are absent from the trans isomer of 9,10-octadecenoamide. One of the most potent actions of oleamide is vasodilation. In rat small mesenteric artery the response

does not involve CB(1) cannabinoid receptors

but another pertussis toxin-sensitive,

G protein-coupled receptor, as yet unidentified.

This receptor is sensitive to rimonabant and O-1918, an antagonist at the putative “abnormal-cannabidiol” or endothelial “anandamide” receptors.

Vasodilation is mediated by endothelium-derived nitric oxide, endothelium-dependent hyperpolarization, and also through activation of TRPV1 receptors. A physiological role for oleamide in the heart and circulation has yet to be demonstrated, as has production by cells of the cardiovascular system, but this molecule has a range of actions that could give it considerable modulatory power.

See also:

Br J Pharmacol. 2006 Mar;147(5):560-8.

Links

Vasorelaxant effects of oleamide in rat small mesenteric artery indicate action at a novel cannabinoid receptor.

Hoi PM, Hiley CR.

Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.

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Wei et al 2006

J Biol Chem. 2006 Dec 1;281(48):36569-78. Epub 2006 Oct 2.

Links

A second fatty acid amide hydrolase with variable distribution among placental mammals.

Wei BQ, Mikkelsen TS, McKinney MK, Lander ES, Cravatt BF.

The Skaggs Institute for Chemical Biology and Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.

Fatty acid amides

…..constitute a large and diverse class

……of lipid transmitters

… that includes the endogenous cannabinoid anandamide

….and the sleep-inducing substance oleamide.

The magnitude and duration of fatty acid amide signaling are controlled by enzymatic hydrolysis in vivo.

…..Fatty acid amide hydrolase (FAAH) activity in mammals has been primarily attributed to a single integral membrane enzyme of the amidase signature (AS) family.

Here, we report the functional proteomic discovery of a second membrane-associated AS enzyme in humans that displays FAAH activity.

The gene that encodes this second FAAH enzyme

…..was found in multiple primate genomes, marsupials, and more distantly related vertebrates,

…… but, remarkably, not in a number of lower placental mammals, including mouse and rat.

The two human FAAH enzymes,

…..which share 20% sequence identity and are referred to hereafter as FAAH-1 and FAAH-2,

….hydrolyzed primary fatty acid amide substrates (e.g. oleamide) at equivalent rates,

……….whereas FAAH-1 exhibited much greater activity with N-acyl ethanolamines (e.g. anandamide) and N-acyl taurines.

Both enzymes were sensitive to the principal classes of FAAH inhibitors synthesized to date, including O-aryl carbamates and alpha-keto heterocycles. These data coupled with the

…..overlapping, but distinct tissue distributions of FAAH-1 and FAAH-2

…………suggest that these proteins may collaborate to control fatty acid amide catabolism in primates.

The apparent loss of the FAAH-2 gene

…..in some lower mammals should be taken into consideration when extrapolating genetic or pharmacological findings on the fatty acid amide signaling system across species.

+++++++++++++++++++++++

Li & Wang 2006

J Hypertens. 2006 Nov;24(11):2271-6.

Links

Differential mechanisms mediating depressor and diuretic effects of anandamide.

Li J, Wang DH.

Department of Medicine and Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA.

BACKGROUND: Anandamide (AEA), one of the endocannabinoid compounds, has an

important regulatory function by

serving as an autocrine/paracrine or endocrine factor throughout the body

via activation of the cannabinoid receptor 1 (CB1) and/or the transient receptor potential vanilloid type 1 (TRPV1) channels.

However, the role of AEA in the regulation of renal excretory function is largely unknown. The present study was designed to test the hypothesis that intrarenal administration of AEA enhances renal excretory function leading to a decrease in blood pressure.

. CONCLUSIONS: Therefore, our data show that intramedullary infusion of AEA increases urine volume excretion and decreases blood pressure via distinct operational mechanisms. While activation of the CB1 receptor may underlie AEA-induced depressor effects,

the diuretic effect of AEA appears to be mediated by neuronal reflex of the kidney, which is not sensitive to blockade of the TRPV1 or CB1 receptor.

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del Carmen Garcia, Adler-Graschinsky & Celuch 2003

Naunyn Schmiedebergs Arch Pharmacol. 2003 Oct;368(4):270-6. Epub 2003 Sep 18.

Links

Hypotensive effect of anandamide through the activation of CB1 and VR1 spinal receptors in urethane-anesthetized rats.

del Carmen García M, Adler-Graschinsky E, Celuch SM.

Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, University of Buenos Aires, Buenos Aires, Argentina.

… Either anandamide or its metabolically stable analogue methanandamide (25 to 100 nmol) produced dose-dependent decreases in the blood pressure that persisted at least for up to 30 min. … results suggest that anandamide could modulate the blood pressure through the activation of cannabinoid CB(1) receptors and vanilloid VR(1) receptors localized at the spinal cord.

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Gorzalka, Hill & Hillard 2008

J Neural Transm. 2008 Dec;115(12):1673-9. Epub 2008 Oct 31.

Links

Erratum in:

J Neural Transm. 2009 Feb;116(2):141.

Differential effects of the antidepressants tranylcypromine and fluoxetine on limbic cannabinoid receptor binding and endocannabinoid contents.

Hill MN, Ho WS, Hillard CJ, Gorzalka BB.

Department of Psychology, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada. mhill_psych_ubc@hotmail.com

The endocannabinoid system is a widely distributed,

….neuromodulatory system which serves an integral role in regulating synaptic transmission.

The presence of this system in stress-responsive neural circuits suggests that it may play a critical role in regulating neuroendocrine and behavioral responses to stress.

Endocannabinoid content in limbic structures which regulate activation of the hypothalamic-pituitary-adrenal (HPA) axis is dynamically regulated by stress.

Under conditions of acute stress,

the endocannabinoid system tonically constrains activation of the HPA axis.

During repeated exposure to aversive stimuli,

the endocannabinoid system up-regulates in limbic structures,

resulting in dampened neural activity in stress circuits,

which could contribute to stress habituation.

Disrupted endocannabinoid signaling,

on the other hand, is associated with an

inability to adapt to chronic stress.

Therapeutically, these data suggest that

the endocannabinoid system

could be dysregulated in affective disorders, such as depression,

which are characterized by maladaptive stress coping.

In this review, we discuss the evidence demonstrating that the

endocannabinoid system is affected by and can oppose the effects of prolonged stress

and, as such, represents a potential target for the development of novel antidepressant agents.

Linda note:  I must suffer from magical thinking in that I want to believe that as researchers get this close to understanding exactly where, what, how our bodies are responding to stress that this information somehow ALONE has power to affect healing change without having to resort to even newer kinds of medication to change how things are happening in our bodies.

This information is saying that it is not the HPA axis dysregulation that is at the core of our discomfort – the dysregulation is in the endocannabinoid system.  When I read research that says this system’s effects on our bones is the most important action to consider, it makes me wonder.  Evidently it is RIGHT HERE that the dysregulation of our emotions begins when we do not receive what we need from birth as our brains are growing.

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See also:

Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment.

Hill MN, Carrier EJ, McLaughlin RJ, Morrish AC, Meier SE, Hillard CJ, Gorzalka BB.

J Neurochem. 2008 Sep;106(6):2322-36. Epub 2008 Jul 15.

PMID: 18643796 [PubMed – indexed for MEDLINE]

Related Articles

Regulation of endocannabinoid signaling by stress: implications for stress-related affective disorders.

Gorzalka BB, Hill MN, Hillard CJ.

Neurosci Biobehav Rev. 2008 Aug;32(6):1152-60. Epub 2008 Mar 18. Review.

PMID: 18433869 [PubMed – indexed for MEDLINE]

Related Articles

Serum endocannabinoid content is altered in females with depressive disorders: a preliminary report.

Hill MN, Miller GE, Ho WS, Gorzalka BB, Hillard CJ.

Pharmacopsychiatry. 2008 Mar;41(2):48-53.

PMID: 18311684 [PubMed – indexed for MEDLINE]

Related Articles

Prolonged glucocorticoid treatment decreases cannabinoid CB1 receptor density in the hippocampus.

Hill MN, Carrier EJ, Ho WS, Shi L, Patel S, Gorzalka BB, Hillard CJ.

Hippocampus. 2008;18(2):221-6.

PMID: 18058925 [PubMed – indexed for MEDLINE]

Related Articles

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Wenger & Moldrich 2002

Abstract – Department of Human Morphology and Developmental Embryology, Semmelweis University Budapest, Tüzoltó u.58, PO Box 95, H-1450 Budapest, Hungary. wenger@ana2.sote.hu

The hypothalamus

plays an important role in the regulation of several visceral processes, including food intake,

thermoregulation and

control of anterior pituitary secretion.

Endogenous cannabinoids and CB(1) cannabinoid receptors have been found in the hypothalamus.

In the present review, we would like to clarify the role of the endocannabinoid system in the regulation of the above-mentioned visceral functions.

There is historical support for the role of marihuana (i.e. exogenous cannabinoids) in the regulation of appetite. Endocannabinoids also stimulate food intake. Furthermore, the specific CB(1) receptor antagonist SR141716 reduces food intake. Leptin treatment decreases endocannabinoid levels in normal rats and ob/ob mice. These findings provide evidence for the role of the hypothalamic endocannabinoid system in food intake and appetite regulation.

Cannabinoids can change

body temperature

in a dose-dependent manner.

,,,,, High doses cause hypothermia while low doses cause hyperthermia.

Cannabinoid administration decreases heat production. It seems that the effects of cannabinoids on thermoregulation is

….exerted by altering some neurochemical mediator effects at both the presynaptic and postsynaptic level.

THC and endocannabinoids have mainly inhibitory effects on the regulation of reproduction.

…..Administration of anandamide (AEA) decreases serum luteinizing hormone (LH) and prolactin (PRL) levels.

….AEA causes a prolongation of pregnancy in rats and temporarily inhibits the postnatal development of the hypothalamo-pituitary axis in offspring.

The action of AEA on the reproductory parameters occurs at both the hypothalamic and pituitary level.

CB(1) receptors have also been found in the anterior pituitary.

Further, LH levels in CB(1) receptor-inactivated mice were decreased compared with wild-type mice. Taken together, all these observations suggest that the endocannabinoid system is playing an important part in the regulation of the mentioned visceral functions and it provides the bases for further applications of cannabinoid receptor agonists and/or antagonists in visceral diseases regulated by the hypothalamus.

+++++++++++++++++++

See also:

Methods Mol Med. 2006;123:269-90.

Links

Behavioral methods in cannabinoid research.

Fride E, Perchuk A, Hall FS, Uhl GR, Onaivi ES.

Department of Behavioral Sciences, College of Judea and Samaria, Ariel, Israel.

++++++++++++++++++++

Bequet et al 2007

Eur J Neurosci. 2007 Dec;26(12):3458-64. Epub 2007 Dec 4.

Links

CB1 receptor-mediated control of the release of endocannabinoids (as assessed by microdialysis coupled with LC/MS) in the rat hypothalamus.

Béquet F, Uzabiaga F, Desbazeille M, Ludwiczak P, Maftouh M, Picard C, Scatton B, Le Fur G.

Discovery Analytics, sanofi-aventis R&D, 195 route d’Espagne, BP1169 31036 Toulouse cedex 1, France. frederic.bequet@sanofi-aventis.com

In the present study, we examined the occurrence and potential regulation of endocannabinoid release by cannabinoid CB1 receptors in the rat brain. ….

CB1 receptors are able to control the local release of endocannabinoids

in the hypothalamus

via a feedback mechanism

and strengthen the view that anandamide and 2-arachidonoyl-glycerol

have distinct physiological roles.

+++++++++++++++++++

Panatier et al 2006

J Physiol. 2006 Jun 15;573(Pt 3):711-21. Epub 2006 Apr 13.

Links

Activity-dependent synaptic plasticity in the supraoptic nucleus of the rat hypothalamus.

Panatier A, Gentles SJ, Bourque CW, Oliet SH.

INSERM U378, 33077 Bordeaux, France.

Activity-dependent long-term synaptic changes were investigated at glutamatergic synapses in the supraoptic nucleus (SON) of the rat hypothalamus. In acute hypothalamic slices, high frequency stimulation (HFS) of afferent fibers caused long-term potentiation (LTP) of the amplitude of AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) recorded with the whole-cell patch-clamp technique. LTP was also obtained in response to membrane depolarization paired with mild afferent stimulation. On the other hand, stimulating the inputs at 5 Hz for 3 min at resting membrane potential caused long-term depression (LTD) of excitatory transmission in the SON.

These forms of synaptic plasticity required the activation of NMDA receptors since they were abolished in the presence of D-AP5 or ifenprodil, two selective blockers of these receptors. Analysis of paired-pulse facilitation and trial-to-trial variability indicated that LTP and LTD were not associated with changes in the probability of transmitter release, thereby suggesting that the locus of expression of these phenomena was postsynaptic. Using sharp microelectrode recordings in a hypothalamic explant preparation, we found that HFS also generates LTP at functionally defined glutamatergic synapses formed between the organum vasculosum lamina terminalis and SON neurons. Taken together, our findings indicate that

glutamatergic synapses in the SON exhibit activity-dependent long-term synaptic changes similar to those prevailing in other brain areas. Such forms of plasticity could play an important role in the context of physiological responses, like dehydration or lactation, where the activity of presynaptic glutamatergic neurons is strongly increased.

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Rawls et al 2002

J Pharmacol Exp Ther. 2002 Jun;301(3):963-8.

Links

CB1 receptors in the preoptic anterior hypothalamus regulate WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one]-induced hypothermia.

Rawls SM, Cabassa J, Geller EB, Adler MW.

Department of Pharmacology, Center for Substance Abuse Research, Temple University School of Medicine, 3420 N. Broad Street, Philadelphia, PA 19140, USA. smrawls28@hotmail.com

The present study investigated the effect of the selective cannabinoid agonist, WIN 55212-2 …, on body temperature. WIN 55212-2 … induced hypothermia in a dose-dependent manner.

The peak hypothermia occurred 60 to 180 min postinjection. Body temperature was still suppressed 5 h after the injection of the highest dose of WIN 55212-2. The selective CB(1) antagonist, SR141716A … blocked the WIN 55212-2-induced hypothermia, suggesting that

CB(1) receptor activation mediated the hypothermia.

In contrast, the selective CB(2) antagonist, SR144528 [N-((1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide)] (5 mg/kg, i.m.), did not alter the WIN 55212-2-induced hypothermia. Neither SR141716A nor SR144528 alone altered body temperature. WIN 55212-2 (1-30 microg/microl) injected directly into the preoptic anterior hypothalamic nucleus (POAH) induced hypothermia in an immediate and dose-dependent fashion. The hypothermia produced by intra-POAH injection of WIN 55212-2 was brief, with body temperature returning to baseline 60 min postinjection. SR141716A (5 mg/kg, i.m.) abolished the hypothermia induced by intra-POAH injection of WIN 55212-2 (30 microg/microl), indicating that CB(1) receptors in the POAH mediated the hypothermia.

The present results confirm the idea that CB(1) receptors mediate the hypothermic response to cannabinoid agonists. Moreover, the present data suggest that

1) the preoptic anterior hypothalamic nucleus (POAH)

is the central locus for thermoregulation, and

2) CB(1) receptors within the

preoptic anterior hypothalamic nucleus (POAH)

are the primary mediators of cannabinoid-induced hypothermia.

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Gonzalez et al 2000

Biochem Biophys Res Commun. 2000 Apr 2;270(1):260-6.

Links

Sex steroid influence on cannabinoid CB(1) receptor mRNA and endocannabinoid levels in the anterior pituitary gland.

González S, Bisogno T, Wenger T, Manzanares J, Milone A, Berrendero F, Di Marzo V, Ramos JA, Fernández-Ruiz JJ.

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, 28040-, Spain.

Recent studies have demonstrated the occurrence of endocannabinoid synthesis and of gene expression and immunoreactivity for the cannabinoid CB(1) receptor in the anterior pituitary gland.

…males had higher levels of CB(1) receptor-mRNA transcripts than females. In addition,

these transcripts fluctuated in females during the different phases of the ovarian cycle, with the highest values observed on the second day of diestrus and the lowest on estrus.

In these animals, we also measured the content of endocannabinoids in the anterior pituitary gland and the hypothalamus. We observed that

females had higher contents of anandamide than males in both cases.

The content of anandamide in females also fluctuated during the ovarian cycle in both the anterior pituitary gland and the hypothalamus. The highest values in the anterior pituitary gland were found in the estrus and the lowest on the first day of diestrus and proestrus, whereas the inverse tendency was found in the hypothalamus.

…. influence of circulating sex steroids on CB(1) receptor gene expression in the anterior pituitary gland….

expression of the CB(1) receptor gene in the anterior pituitary gland is regulated by sex steroids in both males and females.

Furthermore, gonadal steroids appear to affect the response of this gene to chronic cannabinoid administration. We have also observed that anandamide contents in the anterior pituitary gland and the hypothalamus might be controlled by circulating sex steroids. The functional implications of these data are discussed.

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See also:

Neuroendocrinology. 1999 Aug;70(2):137-45.

Links

Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland.

González S, Manzanares J, Berrendero F, Wenger T, Corchero J, Bisogno T, Romero J, Fuentes JA, Di Marzo V, Ramos JA, Fernández-Ruiz J.

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Pluridisciplinar, Universidad Complutense de Madrid, Spain.

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SLEEP PROCESSES

++++

Huitron-Resendiz et al 2004

Sleep. 2004 Aug 1;27(5):857-65.

Links

Characterization of the sleep-wake patterns in mice lacking fatty acid amide hydrolase.

Huitron-Resendiz S, Sanchez-Alavez M, Wills DN, Cravatt BF, Henriksen SJ.

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.

Oleamide and anandamide

……are fatty acid amides

…..implicated in the regulatory mechanisms of

sleep processes.

However, due to their prompt catabolism by fatty acid amide hydrolase (FAAH), their pharmacologic and behavioral effects, in vivo, disappear rapidly.

CONCLUSION: These findings support

….the role of fatty acid amides as possible modulators of sleep

……and indicate that the homeostatic mechanisms of sleep in FAAH (-/-) mice are not disrupted.

+++++++++++++++++++++++++++

J Pharmacol Exp Ther. 2002 Jul;302(1):73-9.

Links

Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo.

Lichtman AH, Hawkins EG, Griffin G, Cravatt BF.

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.

Fatty acid amides (FAAs) represent a class of neuromodulatory lipids that includes the endocannabinoid anandamide and the sleep-inducing substance oleamide. Both anandamide and oleamide produce behavioral effects indicative of cannabinoid activity, but only anandamide binds the cannabinoid (CB1) receptor in vitro.

+++++++++++++++++++++++++++++

Murrillo-Rodriguez et al 2007

Eur J Pharmacol. 2007 May 7;562(1-2):82-91. Epub 2007 Feb 8.

Links

Effects of the fatty acid amide hydrolase inhibitor URB597 on the sleep-wake cycle, c-Fos expression and dopamine levels of the rat.

Murillo-Rodríguez E, Vázquez E, Millán-Aldaco D, Palomero-Rivero M, Drucker-Colin R.

Depto de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, México. emurillo@ifc.unam.mx

Our group has described previously that the

endogenous cannabinoid anandamide induces sleep.

The hydrolysis of this lipid involves the activity of the fatty acid amide hydrolase (FAAH), which additionally catalyzes the degradation of the satiety factor oleoylethanolamide and the analgesic-inducing lipid palmitoylethanolamide

………..It has been demonstrated that the inhibition of the FAAH by URB597 increases levels of anandamide, oleoylethanolamide and palmitoylethanolamide in the brain of rats. In order to determinate the physiological properties of the FAAH inhibition on the sleep modulation, we report the pharmacological effects on the sleep-wake cycle of the rat after i.c.v. administrations of URB597, oleoylethanolamide or palmitoylethanolamide (10, 20 microg/5 microl). Separate unilateral i.c.v. injections of 3 compounds during the lights-on period, increased wakefulness and decreased slow wave (SW) sleep in rats in a dose-dependent fashion. We additionally found out that, compared to controls, c-Fos immunoreactivity in hypothalamus and dorsal raphe nucleus was increased in rats that received URB597, oleoylethanolamide or palmitoylethanolamide (10, 20 microg/5 microl, i.c.v.). Next, we found that after an injection of the compounds, levels of dopamine were increased whereas extracellular levels of levodopa (l-DOPA) were decreased. These findings indicate that that inhibition of the FAAH, via URB597, modulates waking. These effects were mimicked separately by the administration of oleoylethanolamide or palmitoylethanolamide. The alertness induced by the compounds tested here activated wake-promoting brain regions and they also induced the release of dopamine.

Our results suggest that FAAH activity as well as two molecules that are catalyzed by this enzyme, oleoylethanolamide and palmitoylethanolamide, participate in the regulation of the waking state. Alternative approaches to treat sleep disorders such as excessive somnolence might consider the use of the URB597, oleoylethanolamide or palmitoylethanolamide since all compounds enhance waking.

+++++++++++++++++++++++++++++++

FEBS Lett. 2006 Aug 7;580(18):4337-45. Epub 2006 Jul 10.

Links

Cannabidiol, a constituent of Cannabis sativa, modulates sleep in rats.

Murillo-Rodríguez E, Millán-Aldaco D, Palomero-Rivero M, Mechoulam R, Drucker-Colín R.

Depto de Neurociencias, Instituto de Fisiología Celular, Ciudad Universitaria, Circuito Interior, Universidad Nacional Autónoma de México, México DF, CP 04510, Mexico. emurillo@ifc.unam.mx

Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabidiol (CBD) are two major constituents of Cannabis sativa. Delta(9)-THC modulates sleep,…

In conclusion, we found that CBD modulates waking via activation of neurons in the hypothalamus and DRD. Both regions are apparently involved in the generation of alertness. Also, CBD increases DA levels as measured by microdialysis and HPLC procedures. Since CBD induces alertness, it might be of therapeutic value in sleep disorders such as excessive somnolence.

+++++++++++++++++++++++++++++++

Murrillo-Rodriguez et al 2008

Neuroscience. 2008 Nov 11;157(1):1-11. Epub 2008 Sep 4.

Links

The anandamide membrane transporter inhibitor, VDM-11, modulates sleep and c-Fos expression in the rat brain.

Murillo-Rodríguez E, Millán-Aldaco D, Di Marzo V, Drucker-Colín R.

Laboratorio de Neurobiología, Facultad de Medicina, Universidad Autónoma de Campeche, Campeche, Mexico. emurillo@uacam.mx

Endogenous cannabinoids or endocannabinoids are lipid molecules that have a variety of biological actions, most notably via activation of the cannabinoid receptors. The

family of endocannabinoids includes arachidonoylethanolamide (ANA) which modulates different behaviors, such as sleep.

However, it is unknown whether pharmacological elevation of ANA endogenous levels might induce sleep. VDM 11 [(5 Z,8 Z,11 Z,14 Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide] is commonly used as an inhibitor of ANA cellular uptake, and thereby to potentiate its actions. In this study we have examined whether VDM-11 exerts any effect on the sleep-wake cycle and c-Fos expression in brain areas. When assayed alone in rats, VDM-11 (10 or 20 mug/5 muL, i.c.v.) at the beginning of the lights-off period, reduced wakefulness and increased sleep. The CB(1) cannabinoid receptor antagonist, SR141716A, partially reversed the effects of VDM-11 on sleep. Additionally, VDM-11 enhanced c-Fos expression in sleep-related brain areas such as the anterior hypothalamic area, paraventricular thalamic nucleus, and pedunculopontine tegmental nucleus. It is concluded that VDM-11 displays sleep-inducing properties and these effects slightly, albeit significantly, are reversed using SR141716A. Furthermore, c-Fos data suggest a possible underlying neuroanatomical substrate of the sleep-inducing properties of VDM-11. We report evidence suggesting that VDM-11 might be considered for the development of new pharmacological and pharmaceutical approaches to treat sleep disorders such as insomnia.

+++++++++++++++++++++++++++++++

: Prog Neuropsychopharmacol Biol Psychiatry. 2008 Aug 1;32(6):1420-7. Epub 2008 Apr 18.

Links

The role of the CB1 receptor in the regulation of sleep.

Murillo-Rodríguez E.

Laboratorio de Neurobiología, Facultad de Medicina, Universidad Autónoma de Campeche, Campeche, Campeche. Mexico. emurillo@uacam.mx

….Endocannabinoids are fatty acid derivates that have a variety of biological actions, most notably via activation of the cannabinoid receptors. The endocannabinoids have an active role modulating diverse neurobiological functions, such as learning and memory, feeding, pain perception and sleep generation. Experimental evidence shows that the administration of Delta9-THC promotes sleep. The activation of the CB1 receptor leads to an induction of sleep, this effect is blocked via the selective antagonist. Since the system of the endogenous cannabinoids is present in several species, including humans, this leads to the speculation of the neurobiological role of the endocannabinoid system on diverse functions such as sleep modulation. This review discusses the evidence of the system of the endocannabinoids as well as their physiological role in diverse behaviours, including the modulation of sleep.

Murrillo-Rodriguez et al 2008b

Abstract – Depto de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, México. emurillo@ifc.unam.mx

During the 1990s, transmembranal proteins in the central nervous system (CNS) that recognize the principal compound of marijuana, the delta-9-tetrahydrocannabinol (Delta9-THC) were described.

…………The receptors were classified as central or peripheral, CB1 and CB2, respectively.

To this date, it has been documented the presence in the CNS of specific lipids that bind naturally to the CB1/CB2 receptors.

The family of

endogenous cannabinoids or endocannabinoids comprises

oleamide,

arachidonoylethanolamine,

2-arachidonylglycerol,

virodhamine,

noladin ether and

N-arachidonyldopamine.

….Pharmacological experiments have shown that those compounds induce cannabimimetic effects.

……Endocannabinoids are fatty acid derivates that have a variety of biological actions, most notably via activation of the cannabinoid receptors.

The endocannabinoids have an active role modulating diverse neurobiological functions, such as

learning and memory,

feeding,

pain perception and

sleep generation.

Experimental evidence shows that the administration of Delta9-THC promotes sleep. The activation of the CB1 receptor leads to an induction of sleep, this effect is blocked via the selective antagonist. Since the system of the endogenous cannabinoids is present in several species, including humans, this leads to the speculation of the neurobiological role of the endocannabinoid system on diverse functions such as sleep modulation. This review discusses the evidence of the system of the endocannabinoids as well as their physiological role in diverse behaviors, including the modulation of sleep.

Murrillo-Rodriguez et al 2008c – article in Spanish

Abstract – Depto de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, México. emurillo@ifc.unam.mx

The endogenous cannabinoid, or endocannabinoid, system is present in the central nervous system (CNS) of rodents and humans. This system includes receptors, endogenous ligands and enzymes. The presence of cannabinoid receptors, called CB1, in the CNS has been reported in the cerebral cortex, the hippocampus, the cerebellum and the brain stem. This neuroanatomical location suggests that this receptor could modify several physiological functions, such as the consolidation of memory, motor control and the generation of sleep. DEVELOPMENT: Recent reports have described the presence of lipids in the CNS that bind to the CB1 receptor. Administration of said molecules induces cannabimimetic effects, and hence it has been suggested that these lipids are endogenous cannabinoids or endocannabinoids. Anandamide, 2-arachidonylglycerol, virodhamine, noladin ether and N-arachidonyldopamine are molecules that belong to the endocannabinoid family.

Anandamide has received more attention from researchers because it was the first endocannabinoid to be reported. Pharmacological experiments have shown that this endocannabinoid induces several different intracellular and behavioural changes. CONCLUSIONS: In this study, we review the most important pharmacological aspects of exogenous cannabinoids and the neurobiological role played by the endocannabinoid system, including endogenous and exogenous ligands and receptors. We also examine their pharmacological effects on different behaviors, with particular attention given to the modulation of sleep.

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Verty et al 2004

Neuropharmacology. 2004 Sep;47(4):593-603.

Links

Evidence for an interaction between CB1 cannabinoid and oxytocin receptors in food and water intake.

Verty AN, McFarlane JR, McGregor IS, Mallet PE.

School of Psychology, University of New England, Armidale, NSW 2351, Australia

Endocrinology. 2004 Jul;145(7):3224-31. Epub 2004 Mar 19.

Links

Evidence for an interaction between CB1 cannabinoid and melanocortin MCR-4 receptors in regulating food intake.

Verty AN, McFarlane JR, McGregor IS, Mallet PE.

School of Psychology, University of New England, Armidale, New South Wales 2351, Australia

Oxytocin and CB(1) cannabinoid receptors independently modulate food intake.

Although an interaction between oxytocin and cannabinoid systems has been demonstrated with respect to the cannabinoid withdrawal syndrome, the interaction between these systems in modulating food intake has not yet been examined. The present study had three primary purposes: (1) to determine whether oxytocin and a CB(1) receptor antagonist block food and fluid intake in a supra-additive manner, (2) to determine the relative position of the CB(1) receptors in the chain of control of food intake in relation to the oxytocin system, and (3) to determine whether the increase in fluid intake induced by an oxytocin antagonist is mediated via cannabinoid receptors. Rats were habituated to the test environment and injection procedure, and then received intracerebroventricular (ICV) injections of various combinations of the oxytocin receptor antagonist tocinoic acid, the cannabinoid receptor agonist delta(9)-tetrahydrocannabinol (THC), oxytocin, or the cannabinoid receptor antagonist SR 141716. Food and water intake and locomotor activity were then measured for 120 min. When administrated alone, SR 141716 and oxytocin dose-dependently attenuated baseline food intake, while oxytocin but not SR 141716 reduced water intake. Sub-anorectic doses of SR 141716 and oxytocin attenuated baseline feeding beyond what would be expected by the sum of the individual drug effects without affecting baseline water intake. THC stimulated feeding but not water intake. THC-induced feeding was not blocked by oxytocin, however, the oxytocin did attenuate water intake during such feeding. SR 141716 dose-dependently reduced tocinoic-acid-stimulated food intake and partially attenuated water intake. Locomotor activity was not significantly affected by any drug treatments, suggesting that effects on feeding were not due to a non-specific reduction in motivated behavior. These findings reveal

an interaction between cannabinoid and oxytocin systems in food intake. Results further reveal that the oxytocin system effects on water intake are partially mediated via CB(1) receptors, CB(1) receptors are located downstream from oxytocin receptors, and CB(1) receptor signaling is necessary to prevent oxytocin from altering food intake.

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Naunyn Schmiedebergs Arch Pharmacol. 2005 Jan;371(1):9-17. Epub 2005 Jan 20.

Links

Search for an endogenous cannabinoid-mediated effect in the sympathetic nervous system.

Pfitzer T, Niederhoffer N, Szabo B.

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Albertstrasse 25, 79104 Freiburg i. Br., Germany.

Activation of CB(1) cannabinoid receptors by exogenous agonists causes presynaptic inhibition of neurotransmitter release from axon terminals. In the central nervous system, presynaptic CB(1) receptors can also be activated by endogenous cannabinoids (endocannabinoids) released from postsynaptic neurons. Except in the vas deferens, there is no indication of endocannabinoid-mediated presynaptic inhibition in the sympathetic nervous system.

The results verify that activation of peripheral presynaptic CB(1) receptors inhibits noradrenaline release from sympathetic nerve terminals. The lack of effect of the CB(1) receptor antagonist rimonabant indicates that, even under conditions favouring endocannabinoid synthesis, endocannabinoid-mediated presynaptic inhibition is not operating in the sympathetic nervous system of the pithed rat.

See also:

Handb Exp Pharmacol. 2008;(184):435-77.

Links

Presynaptic modulation by endocannabinoids.

Lovinger DM.

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, MD 20892-9411, USA. lovindav@mail.nih.gov

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J Mol Neurosci. 2007 Sep;33(1):87-93.

Links

Endocannabinoid liberation from neurons in transsynaptic signaling.

Lovinger DM.

Laboratory for Integrative Neuroscience, Division of Intramural Clinical and Basic Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA. lovindav@mail.nih.gov

Endocannabinoids are fatty acid derivatives that have a variety of biological actions, most notably via activation of the cannabinoid receptors. These receptors are also targets for drugs derived from Cannabis sativa. In the nervous system, endocannabinoids act as neuromodulators that depress neurotransmitter release at the presynaptic terminal. In most instances of neural endocannabinoid signaling, the compounds appear to be released from the postsynaptic neuron to act on the presynaptic terminal in a “retrograde” manner. Several common mechanisms involved in postsynaptic endocannabinoid production and presynaptic depression produced via activation of the CB1 cannabinoid receptor have been identified. However, significant problems remain in defining the mechanisms underlying endocannabinoid production, release, and movement across the membrane. These issues are discussed in the present review.

PMID: 17901551 [PubMed – indexed for MEDLINE

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Ohno-Shosaku et al 2007

Abstract – Department of Cellular Neuroscience, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan.

Endocannabinoids are released from neurons in activity-dependent manners, act retrogradely on presynaptic CB(1) cannabinoid receptors, and induce short-term or long-term suppression of transmitter release. ….. These data clearly indicate that the activation of NMDA receptors facilitates the endocannabinoid release either alone or in concert with the G(q)-coupled receptors.

See also:

Pharmacological evidence for the involvement of diacylglycerol lipase in depolarization-induced endocanabinoid release.

Hashimotodani Y, Ohno-Shosaku T, Maejima T, Fukami K, Kano M.

Neuropharmacology. 2008 Jan;54(1):58-67. Epub 2007 Jun 22.

PMID: 17655882 [PubMed – indexed for MEDLINE]

Roles of phospholipase Cbeta and NMDA receptor in activity-dependent endocannabinoid release.

Hashimotodani Y, Ohno-Shosaku T, Watanabe M, Kano M.

J Physiol. 2007 Oct 15;584(Pt 2):373-80. Epub 2007 Jul 5.

PMID: 17615097 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Endocannabinoid signalling triggered by NMDA receptor-mediated calcium entry into rat hippocampal neurons.

Ohno-Shosaku T, Hashimotodani Y, Ano M, Takeda S, Tsubokawa H, Kano M.

J Physiol. 2007 Oct 15;584(Pt 2):407-18. Epub 2007 Jul 5.

PMID: 17615096 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Ca(2+)-assisted receptor-driven endocannabinoid release: mechanisms that associate presynaptic and postsynaptic activities.

Hashimotodani Y, Ohno-Shosaku T, Kano M.

Curr Opin Neurobiol. 2007 Jun;17(3):360-5. Epub 2007 Apr 6. Review.

PMID: 17419048 [PubMed – indexed for MEDLINE]

Related Articles

Endocannabinoids and synaptic function in the CNS.

Hashimotodani Y, Ohno-Shosaku T, Kano M.

Neuroscientist. 2007 Apr;13(2):127-37. Review.

PMID: 17404373 [PubMed – indexed for MEDLINE]

Related Articles

Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus.

Hashimotodani Y, Ohno-Shosaku T, Kano M.

J Neurosci. 2007 Jan 31;27(5):1211-9.

PMID: 17267577 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

[Mechanisms of triggering endocannabinoid release]

Hashimotodani Y, Ohno-Shosaku T, Kano M.

Seikagaku. 2006 Feb;78(2):126-30. Japanese. No abstract available.

PMID: 16541803 [PubMed – indexed for MEDLINE]

Related Articles

The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum.

Kawamura Y, Fukaya M, Maejima T, Yoshida T, Miura E, Watanabe M, Ohno-Shosaku T, Kano M.

J Neurosci. 2006 Mar 15;26(11):2991-3001.

PMID: 16540577 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

Synaptically driven endocannabinoid release requires Ca2+-assisted metabotropic glutamate receptor subtype 1 to phospholipase Cbeta4 signaling cascade in the cerebellum.

Maejima T, Oka S, Hashimotodani Y, Ohno-Shosaku T, Aiba A, Wu D, Waku K, Sugiura T, Kano M.

J Neurosci. 2005 Jul 20;25(29):6826-35.

PMID: 16033892 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

Phospholipase Cbeta serves as a coincidence detector through its Ca2+ dependency for triggering retrograde endocannabinoid signal.

Hashimotodani Y, Ohno-Shosaku T, Tsubokawa H, Ogata H, Emoto K, Maejima T, Araishi K, Shin HS, Kano M.

Neuron. 2005 Jan 20;45(2):257-68.

PMID: 15664177 [PubMed – indexed for MEDLINE]

Related Articles

Two distinct classes of muscarinic action on hippocampal inhibitory synapses: M2-mediated direct suppression and M1/M3-mediated indirect suppression through endocannabinoid signalling.

Fukudome Y, Ohno-Shosaku T, Matsui M, Omori Y, Fukaya M, Tsubokawa H, Taketo MM, Watanabe M, Manabe T, Kano M.

Eur J Neurosci. 2004 May;19(10):2682-92.

PMID: 15147302 [PubMed – indexed for MEDLINE]

Related Articles

Presynaptic cannabinoid sensitivity is a major determinant of depolarization-induced retrograde suppression at hippocampal synapses.

Ohno-Shosaku T, Tsubokawa H, Mizushima I, Yoneda N, Zimmer A, Kano M.

J Neurosci. 2002 May 15;22(10):3864-72.

PMID: 12019305 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

Cooperative endocannabinoid production by neuronal depolarization and group I metabotropic glutamate receptor activation.

Ohno-Shosaku T, Shosaku J, Tsubokawa H, Kano M.

Eur J Neurosci. 2002 Mar;15(6):953-61.

PMID: 11918654 [PubMed – indexed for MEDLINE]

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Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals.

Ohno-Shosaku T, Maejima T, Kano M.

Neuron. 2001 Mar;29(3):729-38.

PMID: 11301031 [PubMed – indexed for MEDLINE]

Related Articles

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McKinney & Cravatt 2005

Annu Rev Biochem. 2005;74:411-32.

Links

Structure and function of fatty acid amide hydrolase.

McKinney MK, Cravatt BF.

Departments of Cell Biology and Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA. michele@scripps.edu

Fatty acid amide hydrolase (FAAH)

….is a mammalian integral membrane enzyme

…..that degrades the fatty acid amide family of endogenous signaling lipids,

which includes the

endogenous cannabinoid

….anandamide

….and the sleep-inducing substance oleamide.

FAAH belongs to a large and diverse class of enzymes referred to as the amidase signature (AS) family.

Investigations into the structure and function of FAAH, in combination with complementary studies of other AS enzymes, have engendered provocative molecular models to explain how this enzyme integrates into cell membranes and terminates fatty acid amide signaling in vivo

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Benamar, Geller & Adler 2008

J Pharmacol Exp Ther. 2008 May;325(2):641-5. Epub 2008 Feb 15.

Links

Erratum in:

J Pharmacol Exp Ther. 2008 Jun;325(3):1061.

First in vivo evidence for a functional interaction between chemokine and cannabinoid systems in the brain.

Benamar K, Geller EB, Adler MW.

Center of Substance Abuse Research, Temple University School of Medicine, 3400 N. Broad St., Philadelphia, PA 19140, USA. kbenamar@temple.edu

Growing evidence supports the idea that

…..in addition to their well established role in the immune system,

……chemokines [any of various cytokines produced in acute and chronic inflammation that mobilize and activate white blood cells] might play a role in both normal and pathological brain function,

….and the chemokine network could interact with other neuromodulators.

The chemokine stromal cell-derived growth factor (SDF)-1alpha/CXCL12, a member of the CXC chemokine family,

…..was tested for its possible effect on the analgesic responses of the cannabinoid receptor agonist aminoalkylindole 4,5-dihydro-2-methyl-4-(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo-[3,2,1ij]quinolin-6-one [(+)-WIN 55,212-2, hereafter WIN 55,212-2] at the level of the

periaqueductal gray (PAG),

……a brain region critical to the processing of pain signals, and

….a primary site of action of many analgesic compounds.

This study reports the first in vivo evidence

…..of a functional interaction

….between chemokine and cannabinoid systems in the brain,

……showing that the activation of SDF-1alpha/CXCL12 receptors (CXCR4) in the PAG interferes with the analgesic effects of WIN 55212-2.

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in the fear section:

Martinez et al 2007b

Eur Neuropsychopharmacol. 2007 Nov;17(11):717-24. Epub 2007 Mar 29.

Links

Serotonergic mechanisms in the basolateral amygdala differentially regulate the conditioned and unconditioned fear organized in the periaqueductal gray.

Martinez RC, Ribeiro de Oliveira A, Brandão ML.

Instituto de Neurociências & Comportamento-INeC, Campus USP, 14040-901, Ribeirão Preto, SP, Brazil

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Glaser et al 2005

Vis Neurosci. 2005 Nov-Dec;22(6):693-705.

Links

Endocannabinoids in the intact retina: 3 H-anandamide uptake, fatty acid amide hydrolase immunoreactivity and hydrolysis of anandamide.

Glaser ST, Deutsch DG, Studholme KM, Zimov S, Yazulla S.

Department of Biochemistry and Cell Biology, Stony Brook University, New York 11794-5230, USA.

We conclude that endocannabinoids are present in the goldfish retina and underlay the electrophysiological effects of cannabinoid ligands previously shown on goldfish cones and bipolar cells.

See also:

Klin Oczna. 2008;110(10-12):392-6.

Links

[The role of endocannabinoid system in physiological and pathological processes in the eye]

[Article in Polish]

Nadolska K, Goś R.

Kliniki Okulistyki i Rehabilitacji, Wzrokowej Uniwersytetu Medycznego w Łodzi.

Plant of Cannabis sativa/ marihuana except for its psychotropic effects possesses a range of pharmacological properties, that has been utilized for medical purposes over a period of millenia. Investigations concerning biochemical mechanism of action of the main and most active pharmacological compound of Cannabis sativa, cannabinoid 9-THC, contributed to the discovery of cannabinoid receptors both in the central nervous system (CNS) and peripheral tissues, that mediated actions of this substance. The discovery made possible identification of a new, endogenous signaling system reffered to as the endocannabinoid system. Besides cannabinoid receptors CB1 and CB2, the system includes it’s endogenic ligands (endocannabinoids) and compounds that participate in their biosynthesis and inactivation. Structure and functioning of the endocannabinoid system is conservative in all vertebrates. It’s activation with plant, synthetic and endogenous cannabinoids has an influence on multiple physiological and pathological processes within the eye.

PMID: 19195174 [PubMed – indexed for MEDLINE

Arch Mal Coeur Vaiss. 2006 Mar;99(3):242-6.

Links

The endogenous cardiac cannabinoid system: a new protective mechanism against myocardial ischemia.

Lamontagne D, Lépicier P, Lagneux C, Bouchard JF.

Faculté de pharmacie, Université de Montréal, QC, Canada. daniel.lamontagne@umontreal.ca

Klin Oczna. 2008;110(7-9):314-7.

Links

[Possibilities of applying cannabinoids’ in the treatment of glaucoma]

[Article in Polish]

Nadolska K, Goś R.

Z Kliniki Okulistyki i Rehabilitacji Wzrokowej Uniwersytetu Medycznego, Łodzi.

Over a period of several decades numerous scientific research has proven that, regardless of the route of administration, cannabinoids are able to decrease intraocular pressure. What is more, these compounds are characterized by neuroprotection and vasodilatation properties, that additionally substantiate it’s therapeutic utility in conservative treatment of glaucoma. So far, it has not been described in details what mechanism is used to lower the intraocular pressure by cannabinoids. Nevertheless, the presence of endocannabinoid receptors in structures of the eye responsible for formation and outflow of aqueous humor is an explanation for effectiveness of these compounds, when administered in topical form. These days, with the aid of modern pharmacological technology are available significantly bigger possibilities of improving bioavailability of cannabinoids administered to the eye than in the past, as well as limitation of it’s undesired side effects.

PMID: 19112869 [PubMed – indexed for MEDLINE]

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Nucci et al 2007

Invest Ophthalmol Vis Sci. 2007 Jul;48(7):2997-3004.

Links

Involvement of the endocannabinoid system in retinal damage after high intraocular pressure-induced ischemia in rats.

Nucci C, Gasperi V, Tartaglione R, Cerulli A, Terrinoni A, Bari M, De Simone C, Agrò AF, Morrone LA, Corasaniti MT, Bagetta G, Maccarrone M.

Physiopathological Optics, Department of Biopathology and Diagnostic Imaging, University of Rome Tor Vergata, Rome, Italy.

PURPOSE: To evaluate whether high intraocular pressure (IOP)-induced ischemia [Inadequate blood supply (circulation) to a local area due to blockage of the blood vessels to the area] is associated with modifications in the retinal endocannabinoid metabolism

……and to ascertain whether drugs that interfere with the endocannabinoid system may prevent retinal damage due to ischemic insult.

RESULTS: In rat retina, ischemic insult followed by reperfusion resulted in enhanced FAAH activity and protein expression paralleled by a significant decrease in the endogenous AEA tone, whereas the AEA-membrane transporter or the AEA-synthase NAPE-PLD (N-acyl-phosphatidylethanolamine-hydrolyzing-phospholipase-d) were not affected.

………Retinal ischemia-reperfusion decreased the expression of cannabinoid (CB1) and vanilloid (TRPV1) receptors. Systemic administration of a specific FAAH inhibitor (e.g., URB597) reduced enzyme activity and minimized the retinal damage observed in ischemic-reperfused samples. Similarly, intravitreal injection of the AEA stable analogue, R(+)-methanandamide, reduced cell loss in the RGC layer, and this was prevented by systemic administration of a CB1 or TRPV1 selective antagonist (e.g., SR141716 and capsazepine, respectively).

CONCLUSIONS: The original observation that retinal ischemia-reperfusion [reintroduction of blood flow to organs or tissues after blood flow has been stopped for surgical procedures]

…..reduces endogenous AEA via enhanced expression of FAAH

……..supports the deduction that this is implicated in retinal cell loss caused by high IOP in the RGC layer.

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