*Endocannabinoids, Digestion, Food Intake, Energy Balance

Digestion – cannabinoid, insulin release, obesity

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It may well be that what we call our gut, or visceral body based emotions are also connected to our endogenous ‘naturally occurring’ cannabinoid system.  It would then make perfect sense that people who have lots of pain from past traumas would be drawn to the ‘smoke’ to ease those bodily based powerful emotions.

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The endocannabinoids appear to

….regulate energy balance

….and food intake

….at four functional levels within the brain and periphery:

(i) limbic system (for hedonic evaluation of foods),

(ii) hypothalamus and hindbrain (integrative functions),

(iii) intestinal system, and

(iv) adipose tissue.

At each of these levels,

….the endocannabinoid system interacts

….with a number of better known molecules involved in appetite and weight regulation,

…including leptin, ghrelin, and the melanocortins

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Int J Obes (Lond). 2006 Apr;30 Suppl 1:S30-2.Click here to read Links

The unfolding cannabinoid story on energy homeostasis: central or peripheral site of action?

Horvath TL.

Department of Ob/Gyn and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510-8016, USA.

Presentations in this symposium addressed effects and modes of action of endocannabinoids in various tissues in relation to metabolic disorders. Endocannabinoids are produced and exert their effect in various brain sites, including the mesolimbic reward circuitry and the hypothalamus. Both of these regions have direct ties to energy metabolism regulation, particularly food intake and energy expenditure. These data clearly suggest that the observed beneficial effects of CB1 (cannabinoid receptor 1) receptor antagonists on obesity may be related to the central endocannabinoid system. On the other hand, data presented on cannabinoid action in the liver and white adipose tissues clearly indicate that CB1-mediated events in affecting metabolic phenotype may occur in peripheral tissues as well. This together with the reported results from human trials on CB1 antagonists showing that the initial anorectic effect of rimonabant is diminished after the first weeks while longer lasting weight loss is achieved do indicate that peripheral action of cannabinoids are very important in body weight regulation. Should this hold true in the long run, antagonizing CB1 receptors with compound not crossing the blood-brain barrier could revolutionize pharmaceutical approaches to obesity by offering a tool that short cuts the central nervous system.

PMID: 16570102 [PubMed – indexed for MEDLINE

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Exp Biol Med (Maywood). 2005 Apr;230(4):225-34.

Links

Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood.

Fride E, Bregman T, Kirkham TC.

Department of Behavioral Sciences, College of Judea and Samaria, Ariel, Israel. fride@research.yosh.ac.il

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.

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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

The endocannabinoid system (ECS)

…..consists of two receptors (CB(1) and CB(2)),

….several endogenous ligands (primarily anandamide and 2-AG),

….and over a dozen ligand-metabolizing enzymes.

The ECS has deep phylogenetic [relating to or based on evolutionary development or history] roots

…..and regulates many aspects of embryological development

…..and homeostasis,

…..including neuroprotection and

….neural plasticity,

….immunity and inflammation,

….apoptosis and

…carcinogenesis,

…pain and

….emotional memory

….hunger,

…feeding, and

…metabolism.

The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes and pancreatic islet cells),

…..acting through numerous

,,..,,anorexigenic [reduction in food intake] and

…..orexigenic [appetite stimulant] pathways (e.g.,

…ghrelin,

….leptin,

orexin,

…adiponectin,

….endogenous opioids, and

….corticotropin-releasing hormone).

Obesity leads to excessive endocannabinoid production by adipocytes,

….which drives CB(1) in a feed-forward dysfunction.

Phylogenetic research suggests the

genes for endocannabinoid enzymes,

especially

DAGLalpha and

NAPE-PLD,

may harbor mildly deleterious alleles that express disease-related phenotypes.   Why do they call these mildly deleterious?  Disease is disease – unless they simply mean that they are not, by themselves, life threatening?

Several CB(1) inverse agonists have been developed for the treatment of obesity, including rimonabant, taranabant, and surinabant. These drugs are efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors. However, given the myriad beneficial roles of the ECS, it should be no surprise that systemic CB(1) blockade induces various adverse effects.

Alternatives to systemic blockade include

CB(1) partial agonists,

pleiotropic drugs,

peripherally restricted antagonists,

allosteric antagonists, and

endocannabinoid ligand modulation.

The ECS offers several discrete targets for the management of obesity and its associated cardiometabolic sequelae.

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Despres 2007

Abstract – Québec Heart Institute, Québec QC, Canada. jean-pierre.despres@crhl.ulaval.ca

Recent studies have provided evidence that the endocannabinoid (EC) system has very significant effects on energy balance and metabolism

….. through the central control of appetite

….and by affecting peripheral metabolism.

Endocannabinoids are endogenous phospholipid derivatives which bind and activate cannabinoid receptors type 1 and type 2 (CB1 and CB2 receptors). The CB1 receptor, a G-protein coupled receptor,

…..is believed to be responsible for the majority of the central effects of endocannaboids on appetite.

Chronic positive energy balance and obesity

have been associated with an

……overactivation of the endocannaboid system which has been suggested to contribute to the

……..development of abdominal obesity and to

……associated metabolic abnormalities which increase the

risk of cardiovascular disease and type 2 diabetes.

Animal studies had shown that stimulation of the cannabinoid CB1 receptor with endocannaboids such as anandamide could induce first an increase in food intake leading to body weight gain. Furthermore, an exciting development in this field has been the discovery of CB1 receptors in many peripheral tissues, including key organs involved in carbohydrate and lipid metabolism such as the adipose tissue and liver.

Thus, blocking CB1 receptors located in the liver and adipose tissue could have an additional impact on the metabolic risk profile beyond what could be explained by the reduction in food intake and the related body weight loss.

Preclinical studies have shown that rimonabant, the first CB1-receptor blocker to be available in clinical practice, could not only induce a reduction in food intake, but could also produce body weight loss beyond what could be explained by its effect on food intake. Thus, the evidence from preclinical studies have suggested that CB1 blockade could represent a relevant approach to reduce food intake, to induce body weight loss, and, most importantly,

to “fix” the dysmetabolic state of viscerally obese patients at increased cardiometabolic risk.  But also, as Viveros et al 2008 states, the risk is to “depress” all the other areas that the endocannaboid system helps.

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Cannon 2005

Abstract – 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.

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Kunos 2007

Abstract – National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20817, USA. gkunos@mail.nih.gov

Endogenous endocannabinoids (ECs) (anandamide and 2-arachidonoyl glycerol)

……are part of the leptin-regulated neural circuitry involved in appetite regulation.

One of the sites of the orexigenic action of ECs

…….. involves activation of cannabinoid-1 (CB1) receptors

…… in the lateral hypothalamus,

……from which neurons involved in mediating food reward

…… project into the limbic system.

In animal models of obesity, pharmacologic blockade or genetic ablation of CB1 receptors causes a transient reduction in food intake accompanied by sustained weight loss, reduced adiposity, and

reversal of hormonal/metabolic changes, such as elevated levels of plasma leptin, insulin, glucose, and triglyceride, and reduced levels of plasma adiponectin (Acrp30).

However, the beneficial effects of CB1 blockade on weight and metabolism cannot be explained by appetite suppression alone. Animal studies suggest that CB1 blockade exerts a direct peripheral as well as a central effect on fat metabolism. CB1 receptor blockade with rimonabant has been shown to not only reduce weight and adiposity but also to

directly modulate fat metabolism at peripheral sites in skeletal muscle, adipose tissue, and the liver.

Preclinical animal studies suggest that CB1 blockade acts

……on adipocytes to increase Acrp30 expression,

…..on hepatocytes to decrease de novo lipogenesis and increase fatty acid oxidation, and

……on skeletal muscle to reduce blood glucose and insulin levels.

Extrapolating from animal studies to the clinic, CB1 receptor blockade offers a promising strategy not only for reducing weight and abdominal adiposity but also for preventing and reversing its metabolic consequences.

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Di Marzo & Matias 2005

Nat Neurosci. 2005 May;8(5):585-9.

Links

Endocannabinoid control of food intake and energy balance.

Di Marzo V, Matias I.

Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy. vdimarzo@icmib.na.cnr.it

Marijuana and its major psychotropic component, Delta(9)-tetrahydrocannabinol, stimulate appetite and increase body weight in wasting syndromes, suggesting that the CB(1) cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in controlling energy balance.

The endocannabinoid system controls food intake via both central and peripheral mechanisms, and it may also stimulate lipogenesis and fat accumulation. Here we discuss the multifaceted regulation of energy homeostasis by endocannabinoids, together with its applications to the treatment of eating disorders and metabolic syndromes.

See also:

Endocannabinoids: some like it fat (and sweet too).

Matias I, Cristino L, Di Marzo V.

J Neuroendocrinol. 2008 May;20 Suppl 1:100-9. Review.

PMID: 18426508 [PubMed – indexed for MEDLINE]

Related Articles

Endocannabinoids and the control of energy balance.

Matias I, Di Marzo V.

Trends Endocrinol Metab. 2007 Jan-Feb;18(1):27-37. Epub 2006 Dec 1. Review.

PMID: 17141520 [PubMed – indexed for MEDLINE]

Related Articles

Endocannabinoid synthesis and degradation, and their regulation in the framework of energy balance.

Matias I, Di Marzo V.

J Endocrinol Invest. 2006;29(3 Suppl):15-26. Review.

PMID: 16751706 [PubMed – indexed for MEDLINE]

Related Articles

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Horvath 2006

Int J Obes (Lond). 2006 Apr;30 Suppl 1:S30-2.

Links

The unfolding cannabinoid story on energy homeostasis: central or peripheral site of action?

Horvath TL.

Department of Ob/Gyn and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510-8016, USA.

Presentations in this symposium addressed effects and modes of action of endocannabinoids in various tissues in relation to metabolic disorders.

Endocannabinoids are produced and exert their effect in various brain sites, including the

mesolimbic reward circuitry and the

hypothalamus.

Both of these regions have direct ties to energy metabolism regulation, particularly food intake and energy expenditure.

These data clearly suggest that the observed beneficial effects of CB1 (cannabinoid receptor 1) receptor antagonists on obesity may be related to the central endocannabinoid system.

………On the other hand, data presented on cannabinoid action in the

liver and

white adipose tissues

clearly indicate that CB1-mediated events in affecting metabolic phenotype may occur in peripheral tissues as well. This together with the reported results from human trials on CB1 antagonists showing that the initial anorectic effect of rimonabant is diminished after the first weeks while longer lasting weight loss is achieved do indicate that peripheral action of cannabinoids are very important in body weight regulation.

Should this hold true in the long run, antagonizing CB1 receptors with compound not crossing the blood-brain barrier could revolutionize pharmaceutical approaches to obesity by offering a tool that short cuts the central nervous system.

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Jaeger et al 2008

Dis Markers. 2008;25(1):67-74.

Links

Cannabinoid type-1 receptor gene polymorphisms are associated with central obesity in a Southern Brazilian population.

Jaeger JP, Mattevi VS, Callegari-Jacques SM, Hutz MH.

Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Caixa Postal 15053, 91501-970 Porto Alegre, RS, Brazil.

The CB1 cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in energy balance control, stimulating appetite and increasing body weight in wasting syndromes.

Different studies have investigated the relationship between polymorphisms of the cannabinoid receptor 1 (CNR1) gene and obesity with conflicting results. In the present study, we investigated the 1359G/A (rs1049353), 3813A/G (rs12720071) and 4895A/G (rs806368) polymorphisms in the CNR1 gene in a Brazilian population of European descent. To verify the association between these variants and obesity-related traits in this population, 756 individuals were genotyped by PCR-RFLP methods.

The 4895G allele was associated with waist to hip ratio (WHR)

…. An additive effect with the GAA haplotype was associated with WHR (P = 0.028), although this statistical significance disappeared after Bonferroni correction (P = 0.084). No significant association was observed between the genotypes of the 1359G/A and 3813A/G polymorphisms and any of the quantitative variables investigated. Our findings suggest that

CNR1 gene polymorphism is associated with central obesity in this Brazilian population of European ancestry

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Russo et al 2007

J Clin Endocrinol Metab. 2007 Jun;92(6):2382-6. Epub 2007 Apr 3.

Links

Genetic variations at the endocannabinoid type 1 receptor gene (CNR1) are associated with obesity phenotypes in men.

Russo P, Strazzullo P, Cappuccio FP, Tregouet DA, Lauria F, Loguercio M, Barba G, Versiero M, Siani A.

Unit of Epidemiology and Population Genetics, Institute of Food Sciences, Consiglio Nazionale delle Ricerche, Via Roma 52A/C, Avellino, Italy.

CONTEXT: The endocannabinoid system modulates food intake and body weight in animal models. Treatment with the cannabinoid type 1 receptor blocker, rimonabant, reduces body weight in obese individuals. OBJECTIVE: The aim of this study was to determine whether single nucleotide polymorphisms of the gene encoding cannabinoid type 1 receptor, CNR1, are associated with body fat mass and distribution in two independent samples of white European adult men. DESIGN, SETTING, AND PARTICIPANTS: The 3813A/G and 4895A/G single nucleotide polymorphisms at the exon 4 of CNR1 were genotyped in 930 participants to the Olivetti Prospective Heart Study (OPHS) in Southern Italy and in 216 participants to the Wandsworth Heart and Stroke Study in the United Kingdom. Retrospective analysis was also performed on an OPHS subsample (n = 360) for which anthropometric data from 1987 and 1994-1995 examinations were available. MAIN OUTCOME MEASURES: CNR1 genotypes and anthropometric measures of body fat distribution were determined. RESULTS: In the OPHS study, the 3813G allele was associated with increased subscapular skinfold thickness … and waist circumference (WC) … No association was observed with 4895A/G variant. Haplotype analysis confirmed that the unique haplotype carrying the 3813G was associated with increased WC and subscapular skinfold thickness. Similar results were observed in the OPHS retrospective subsample and the Wandsworth Heart and Stroke Study sample. In the latter, the 3813G was associated with increased WC (96.8 +/- 11.3 vs. 91.6 +/- 10.4 cm; P = 0.006). CONCLUSIONS: Genetic variants at CNR1 are associated with obesity-related phenotypes in men. The detection of polymorphic variants in genes involved in the process of fat accumulation may help identify specific targets for pharmacological treatment of obesity and related metabolic abnormalities.

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Storr & Sharkey 2007

Curr Opin Pharmacol. 2007 Dec;7(6):575-82. Epub 2007 Sep 29.

Links

The endocannabinoid system and gut-brain signalling.

Storr MA, Sharkey KA.

Department of Medicine, Hotchkiss Brain Institute and Institute of Infection, Immunity and Inflammation, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta, Canada.

The endocannabinoid system (ECS) consists of cannabinoid receptors, endogenous ligands and the biosynthetic and metabolic enzymes for their formation and degradation. Within the gastrointestinal (GI) tract, the ECS is involved in the regulation of motility, secretion, sensation, emesis, satiety and inflammation.

Recent studies examining the ECS in the

gut-brain axis

have shed new light on this system and reveal many facets of regulation that are amenable to targeting by pharmacological interventions that may prove valuable for the treatment of GI disorders. In particular, it has been shown that

endocannabinoid levels in the brain and gut

vary according to states of satiety,

and in conditions of diarrhea, emesis and inflammation.

This makes me wonder right here about the connection between the newborn’s opioid and cannabinoid system – that these receptors empty and fill according to the comfort level – or not – of the infant – and are connected at the root of the attachment – and well-being system

This is also important as it ties in with the experience of emotions in the BODY!

The expression of cannabinoid (CB)(1) receptors on vagal afferents

is controlled by the states of satiety

and by gut peptides such as cholecystokinin and ghrelin.

Vagal control of gut motor function and emesis

is regulated by endocannabinoids in the brainstem

acting on CB(1), CB(2) and

transient receptor potential vanilloid (TRPV)-1 receptors.

The ECS is involved

in the modulation of visceral sensation

and likely contributes to

effects of stress on GI function.

This review examines recent developments in our understanding of the

ECS in gut-brain signaling.

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[Not specifically about endocannabinoids, but is related research on the gut-brain axis.  Fascinating to me that it involves the immune system – and I know it is all connected to our experience of gut emotions ]

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Fetissov et al 2008

Nutrition. 2008 Sep;24(9):854-9.

Links

Emerging role of autoantibodies against appetite-regulating neuropeptides in eating disorders.

Fetissov SO, Hamze Sinno M, Coquerel Q, Do Rego JC, Coëffier M, Gilbert D, Hökfelt T, Déchelotte P.

Digestive System and Nutrition Laboratory (ADEN EA3234), Institute of Biomedical Research, Rouen University, IFR23, Rouen, France. Serguei.Fetissov@univ-rouen.fr

Recent findings of autoantibodies [Antibodies that attack parts of your body or your own tissues; produced by a faulty immune system] directed against melanocortin peptides suggest that these autoantibodies may represent a source of variability in peptidergic signaling that can be responsible for altered appetite and emotion in eating disorders.

However, it is still unknown if

autoantibodies directed against some other appetite-regulating neuropeptides and peptide hormones exist in healthy human subjects and if these autoantibodies can regulate appetite and emotion. METHODS: We determined the presence of autoantibodies against some key appetite-regulating neuropeptides and peptide hormones in sera of human subjects and in rats, and used animal models to study the role of alpha-melanocyte-stimulating hormone autoantibodies in food intake and anxiety. RESULTS: Immunoglobulin G and A autoantibodies against alpha-melanocyte-stimulating hormone, neuropeptide Y, agouti-related protein, ghrelin, leptin, and some other neuropeptides or peptide hormones involved in appetite control were present in healthy humans and rats. Animal models including active and passive transfer showed that

alpha-melanocyte-stimulating hormone autoantibodies

are involved in the

regulation of

feeding and

anxiety.

Sequence homology was found between neuropeptides and proteins from some members of intestinal microflora, whereas germ-free rats showed altered levels of autoantibodies directed against several neuropeptides.

CONCLUSION: Autoantibodies directed against appetite-regulating neuropeptides and peptide hormones are emerging as important participants in the peptidergic mechanisms controlling motivated behavior. Furthermore, these

autoantibodies could provide a link in the

gut-brain axis

and may represent new biological targets for the diagnosis and treatment of eating disorders.

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Fetissov et al 2008b

Nutrition. 2008 Apr;24(4):348-59. Epub 2008 Feb 8.

Links

Comment in:

Nutrition. 2009 Mar;25(3):252-4.

Autoantibodies against appetite-regulating peptide hormones and neuropeptides: putative modulation by gut microflora.

Fetissov SO, Hamze Sinno M, Coëffier M, Bole-Feysot C, Ducrotté P, Hökfelt T, Déchelotte P.

Digestive System and Nutrition Laboratory (ADEN EA3234), Institute of Biomedical Research, Rouen University and Hospital, IFRMP23, Rouen, France. Serguei.Fetissov@univ-rouen.fr

Peptide hormones

synthesized in gastrointestinal and adipose tissues

in addition to neuropeptides

regulate appetite and body weight.

Previously, autoantibodies directed against melanocortin peptides were found in patients with eating disorders; however, it remains unknown whether autoantibodies directed against other appetite-regulating peptides are present in human sera and whether their levels are influenced by gut-related antigens. METHODS: Healthy women were studied for the presence of immunoglobulin (Ig) G and IgA autoantibodies directed against 14 key appetite-regulating peptides. The concept of molecular mimicry was applied to search in silico whether bacteria, viruses, or fungi contain proteins with amino acid sequences identical to appetite-regulating peptides. In addition, autoantibodies serum levels were studied in germ-free and specific pathogen-free rats. RESULTS: We found these IgG and IgA autoantibodies directed against leptin, ghrelin, peptide YY, neuropeptide Y, and other appetite-regulating peptides are present in human sera at levels of 100-900 ng/mL. Numerous cases of sequence homology with these peptides were identified among commensal and pathogenic micro-organisms including Lactobacilli, bacteroides, Helicobacter pylori, Escherichia coli, and Candida species. Decreased levels of IgA autoantibodies directed against several appetite-regulating peptides and increased levels of antighrelin IgG were found in germ-free rats compared with specific pathogen-free rats.

CONCLUSION: Healthy humans and rats display autoantibodies directed against appetite-regulating peptide hormones and neuropeptides, suggesting that these autoantibodies may have physiologic implications in hunger and satiety pathways. Gut-related antigens including the intestinal microflora may influence production of theses autoantibodies, suggesting a new link between the gut and appetite control.

See also:

Nutrition. 2008 Sep;24(9):854-9.

Links

Emerging role of autoantibodies against appetite-regulating neuropeptides in eating disorders.

Fetissov SO, Hamze Sinno M, Coquerel Q, Do Rego JC, Coëffier M, Gilbert D, Hökfelt T, Déchelotte P.

Digestive System and Nutrition Laboratory (ADEN EA3234), Institute of Biomedical Research, Rouen University, IFR23, Rouen, France. Serguei.Fetissov@univ-rouen.fr

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Vemuri, Janero & Makriyannis 2008

Physiol Behav. 2008 Mar 18;93(4-5):671-86. Epub 2007 Nov 21.

Links

Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome.

Vemuri VK, Janero DR, Makriyannis A.

Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115-5000, United States

Endogenous signaling lipids (“endocannabinoids”)

functionally related to Delta(9)-tetrahydrocannabinol,

the psychoactive ingredient of marijuana (Cannabis),

are important biomediators

and metabolic regulators critical to mammalian (patho)physiology.

The growing family of endocannabinoids, along with endocannabinoid biosynthetic and inactivating enzymes, transporters, and at least two membrane-bound, G-protein coupled receptors, comprise collectively the mammalian endocannabinoid signaling system.

The ubiquitous and diverse regulatory actions of the endocannabinoid system in health and disease have supported the regulatory approval of natural products and synthetic agents as drugs that alter endocannabinoid-system activity.

More recent data support the concept that the endocananbinoid system may be modulated for therapeutic gain at discrete pharmacological targets with safety and efficacy. Potential medications based on the endocannabinoid system have thus become a central focus of contemporary translational research for varied indications with important unmet medical needs.

One such indication, obesity, is a global pandemic

whose etiology has a pathogenic component of endocannabinoid-system hyperactivity

and for which current pharmacological treatment is severely limited. Application of high-affinity, selective CB1 cannabinoid receptor ligands to attenuate endocannabinoid signaling represents a state-of-the-art approach for improving obesity pharmacotherapy. To this intent, several selective CB1 receptor antagonists with varied chemical structures are currently in advanced preclinical or clinical trials, and one (rimonabant) has been approved as a weight-management drug in some markets.

Emerging preclinical data suggest that CB1 receptor neutral antagonists may represent breakthrough medications superior to antagonists/inverse agonists such as rimonabant for therapeutic attenuation of CB1 receptor transmission.

Since obesity is a predisposing condition for the cluster of cardiovascular and metabolic derangements collectively known as the metabolic syndrome, effective endocannabinoid-modulatory anti-obesity therapeutics would also help redress other major health problems

including type-2 diabetes,

atherothrombosis,

inflammation, and

immune disorders.

Pressing worldwide healthcare needs and increasing appreciation of endocannabinoid biology make the rational design and refinement of targeted CB1 receptor modulators a promising route to future medications with significant therapeutic impact against overweight, obesity, obesity-related cardiometabolic dysregulation, and, more generally, maladies having a reward-supported appetitive component.

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Curr Med Chem. 2006;13(22):2669-80.

Links

Therapeutic potential of targeting the endocannabinoids: implications for the treatment of obesity, metabolic syndrome, drug abuse and smoking cessation.

Tucci SA, Halford JC, Harrold JA, Kirkham TC.

University of Liverpool, Eleanor Rathbone Building, Bedford Street South, Liverpool L69 7ZA, UK. sonia.tucci@liv.ac.uk

Rimonabant (SR141716, Acomplia) has been described as an antagonist/inverse agonist at the cannabinoid receptor type 1 (CB1). It has been widely used as a tool to evaluate the mechanisms by which cannabinoid agonists produce their pharmacological effects and to elucidate the respective physiological or pathophysiological roles of the CB1 receptor. It has become increasingly clear that rimonabant can exert its own intrinsic actions. These may be viewed as evidence of either the inverse agonist nature of rimonabant or of tonic activity of the endocannabinoid system. To date, data obtained from clinical trials (RIO North America, RIO Europe and RIO Lipid) indicate that rimonabant may have clinical benefits in relation to its anti-obesity properties and as a novel candidate for the treatment of metabolic and cardiovascular disorders associated with overweight and obesity. Other clinical trials, such as the STRATUS study, have also shown that rimonabant may be effective in smoking cessation, and that the drug has a reasonable safety profile. Recently, it has been shown that rimonabant prevents indomethacin-induced intestinal injury by decreasing the levels of pro-inflammatory cytokine tumour necrosis factor alpha (TNFalpha), thus indicating that CB1 receptor antagonists might exhibit potential anti-inflammatory activity in acute and chronic diseases.

PMID: 17017918 [PubMed – indexed for MEDLINE

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Fetissov & Dechelotte 2008c

Curr Opin Clin Nutr Metab Care. 2008 Jul;11(4):428-34.

Links

Comment in:

Curr Opin Clin Nutr Metab Care. 2008 Jul;11(4):398-9.

The putative role of neuropeptide autoantibodies in anorexia nervosa.

Fetissov SO, Déchelotte P.

Digestive System & Nutrition Laboratory (ADEN EA3234), Institute of Biomedical Research, Rouen University Hospital and IFRMP23, Rouen, France. Serguei.Fetissov@univ-rouen.fr

Anorexia nervosa remains a disease of unknown etiology. This situation explains the failure to develop effective therapy and emphasizes the fact that the neurobiological mechanisms of appetite and emotion are still incompletely understood. The present review is the first summary of recent research

assigning to the immune system

a new role in energy and emotional regulation

by the production of autoantibodies

directed against neuropeptides.

The results of this research are promising to shed light on the etiology of eating disorders and open new fields for biological diagnosis and follow-up as well as designing new therapeutic strategies. RECENT FINDINGS: Following the initial identification of

autoantibodies against

alpha-melanocyte-stimulating hormone,

a key neuropeptide involved in the regulation

of satiety and mood,

in the plasma of patients with anorexia and bulimia nervosa, it has been further found that the serum levels of these autoantibodies correlated with psychopathological traits in individuals with eating disorders. Furthermore, recent findings show that

autoantibodies against alpha-melanocyte-stimulating hormone and against some other appetite-regulating peptide hormones are normally present in the blood of humans and rats and their production may be influenced by stress and the gut microflora.

SUMMARY: Novel data provide evidence that

autoantibodies against neuropeptides can be involved

in the regulation of

appetite and

emotion

and that alteration in autoantibody-mediated signaling pathways may be responsible for the development of eating disorders.

Linda note:  This information is related to my suspicion that the immune system is the key system that regulates our interactions between our bodies and our environment

See also:

Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14865-70. Epub 2005 Sep 29.

Links

Autoantibodies against neuropeptides are associated with psychological traits in eating disorders.

Fetissov SO, Harro J, Jaanisk M, Järv A, Podar I, Allik J, Nilsson I, Sakthivel P, Lefvert AK, Hökfelt T.

Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden. serguei.fetissov@univ-rouen.fr

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Grieco et al 2006

Peptides. 2006 Feb;27(2):472-81. Epub 2005 Nov 21.

Links

Structure-activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position.

Grieco P, Cai M, Mayorov AV, Trivedi D, Hruby VJ.

Department of Chemistry and Toxicology, University of Arizona, Tuscon, AZ 85721, USA.

Cyclic melanotropin peptides, designed with an aromatic amino acid substitution at the N-terminal position of the MT-II-type scaffold, were prepared by solid-phase peptide synthesis and evaluated for their ability to bind to and activate human melanocortin-1, -3, -4, and -5 receptors. The structure-activity studies of these MT-II analogues have identified a selective antagonist at the hMC4R (H-Phe-c[Asp-Pro-d-Nal(2′)-Arg-Trp-Gly-Lys]-NH(2), pA(2)=8.7), a selective partial agonist at the hMC4R (H-d-Nal(2′)-c[Asp-Pro-d-Phe-Arg-Trp-Gly-Lys]-NH(2), IC(50)=11nM, EC(50)=56nM), and a selective partial agonist at the hMC3R (H-d-Phe-c[Asp-Pro-d-Phe-Arg-Trp-Lys]-NH(2), IC(50)=3.7nM, EC(50)=4.9nM). Aromatic amino acid substitution at the N-terminus in conjunction with the expansion of the 23-membered cyclic lactam MT-II scaffold to a 26-membered scaffold by addition of a Gly residue in position 10 leads to melanotropin peptides with enhanced receptor selectivity.

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Starowicz et al 2008

From abstract – Italy

Article title:  Endocannabinoid dysregulation in the pancreas and adipose tissue of mice fed with a high-fat diet.

OBJECTIVE: In mice, endocannabinoids (ECs)

….modulate insulin release from pancreatic beta-cells

……and adipokine [a group of cytokines (cell-to-cell signalling proteins) secreted by adipose tissue] expression in adipocytes [the scientific term for fat cells, being various types of specialized cells found in adipose tissue used for fat storage] through cannabinoid receptors.

Their pancreatic and adipose tissue levels are elevated during hyperglycemia and obesity,

but the mechanisms underlying these alterations are not understood. METHODS AND PROCEDURES: We assessed in mice fed for up to 14 weeks with a standard or high-fat diet

DISCUSSION: We provide unprecedented information on the

…..distribution of [endocannabinoid] EC metabolic enzymes in the pancreas and adipose organ,

……..where their aberrant expression during hyperglycemia and obesity contribute to dysregulated [endocannabinoid] EC levels.

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see also:

Endocannabinoids in adipocytes during differentiation and their role in glucose uptake.

Gasperi V, Fezza F, Pasquariello N, Bari M, Oddi S, Agrò AF, Maccarrone M.

Cell Mol Life Sci. 2007 Jan;64(2):219-29.

PMID: 17187172 [PubMed – indexed for MEDLINE]

Related Articles

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Matias et al 2008

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.

Endocannabinoids are paracrine/autocrine lipid mediators with several biological functions. One of these, i.e. the capability to stimulate food intake via cannabinoid CB(1) receptors, has been particularly studied, thus leading to the development of the first CB(1) receptor blocker, rimonabant, as a therapeutic tool against obesity and related metabolic disorders.

Hypothalamic endocannabinoids

stimulate appetite by regulating the expression and release of anorexic and orexigenic neuropeptides via CB(1) receptors. In turn, the

tone of the latter receptors is regulated by hormones, including leptin, glucocorticoids and possibly ghrelin and neuropeptide Y,

………..by modulating the biosynthesis of the endocannabinoids in various areas of the hypothalamus. CB(1) receptor stimulation is also known to increase blood glucose during an oral glucose tolerance test in rats.

Here we investigated in the rat if

insulin, which is known to

exert fundamental actions

at the level of the mediobasal hypothalamus (MBH), and the

melanocortin system,

namely alpha-melanocyte stimulating hormone (alpha-MSH)

and melanocortin receptor-4 (MCR-4),

[nope!] also regulate hypothalamic endocannabinoid levels,

measured by isotope-dilution liquid chromatography coupled to mass spectrometry. No effect on anandamide and 2-arachidonoylglycerol levels was observed after 2h infusion of insulin in the MBH, i.e. under conditions in which the hormone reduces blood glucose, nor with intra-cerebroventricular injection of alpha-MSH, under conditions in which the neuropeptide reduces food intake. Conversely, blockade of MCR-4 receptors with HS014 produced a late (6h after systemic administration) stimulatory effect on endocannabinoid levels as opposed to a rapid and prolonged stimulation of food-intake (observable 2 and 6h after administration). These data suggest that inhibition of endocannabinoid levels does not mediate the effect of insulin on hepatic glucose production nor the food intake-inhibitory effect of alpha-MSH, ……….although stimulation of endocannabinoid levels might underlie part of the late stimulatory effects of MCR-4 blockade on food intake.

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Nutr Res. 2008 Oct;28(10):641-50.

Links

Endocannabinoids, metabolic regulation, and the role of diet.

Carr TP, Jesch ED, Brown AW.

Department of Nutrition and Health Sciences, University of Nebraska, Lincoln, NE 68583-0806, USA. tcarr2@unl.edu

Understanding the endocannabinoid system as it relates to health and disease is a relatively new area of study. The discovery and cloning of cannabinoid receptors have prompted an increase in research aimed at identifying endogenous ligands (“endocannabinoids”) and how these receptors and ligands regulate a variety of physiologic and pathologic events that include bone formation, the cardiovascular system, appetite control, and energy metabolism. With regard to nutrition, researchers have begun to ask whether the known effects of diet on metabolic processes are mediated through endocannabinoids and their receptors. Although only a few studies have been conducted that directly address the role of diet, results indicate that endocannabinoids can be regulated by eating frequency and by specific dietary components, particularly fatty acids. This review provides an overview of the endocannabinoid system and its control of metabolism, with emphasis on the impact of diet.

PMID: 19083471 [PubMed – indexed for MEDLINE

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Prog Brain Res. 2006;153:367-405.

Links

Hypothalamic integration of immune function and metabolism.

Guijarro A, Laviano A, Meguid MM.

Surgical Metabolism and Nutrition Laboratory, Neuroscience Program, University Hospital, SUNY Upstate Medical University, 750 Adams St., Syracuse, NY 13210, USA.

The immune and neuroendocrine systems are closely involved in the regulation of metabolism at peripheral and central hypothalamic levels. In both physiological (meals) and pathological (infections, traumas and tumors) conditions immune cells are activated responding with the release of cytokines and other immune mediators (afferent signals). In the hypothalamus (central integration), cytokines influence metabolism by acting on nucleus involved in feeding and homeostasis regulation leading to the acute phase response (efferent signals) aimed to maintain the body integrity. Peripheral administration of cytokines, inoculation of tumor and induction of infection alter, by means of cytokine action, the normal pattern of food intake affecting meal size and meal number suggesting that cytokines acted differentially on specific hypothalamic neurons. The effect of cytokines-related cancer anorexia is also exerted peripherally. Increase plasma concentrations of insulin and free tryptophan and decrease gastric emptying and d-xylose absorption. In addition, in obesity an increase in interleukin (IL)-1 and IL-6 occurs in mesenteric fat tissue, which together with an increase in corticosterone, is associated with hyperglycemia, dyslipidemias and insulin resistance of obesity-related metabolic syndrome. These changes in circulating nutrients and hormones are sensed by hypothalamic neurons that influence food intake and metabolism……….

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Soria-Gomez et al 2007

Br J Pharmacol. 2007 Aug;151(7):1109-16. Epub 2007 Jun 4.

Links

Pharmacological enhancement of the endocannabinoid system in the nucleus accumbens shell stimulates food intake and increases c-Fos expression in the hypothalamus.

Soria-Gómez E, Matias I, Rueda-Orozco PE, Cisneros M, Petrosino S, Navarro L, Di Marzo V, Prospéro-García O.

Grupo de Neurociencias, Depto. de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico DF 04510, Mexico.

Evidence indicates that the endocannabinoid, 2-arachidonoylglycerol (2-AG), increases food intake when injected into the nucleus accumbens shell (NAcS), thereby potentially activating hypothalamic nuclei involved in food intake regulation

CONCLUSIONS AND IMPLICATIONS: These data support the

involvement of the endocannabinoid system in feeding behavior at the level of the NAcS and hypothalamus. In addition, this is the first experimental demonstration that the pharmacological inhibition of endocannabinoid inactivation in the NAcS stimulates food intake, suggesting that the endocannabinoid degrading proteins can be a target for treating eating disorders.

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PANCREAS

Bermúdez-Silva et al 2008

Presence of functional cannabinoid receptors in human endocrine pancreas.

Bermúdez-Silva FJ, Suárez J, Baixeras E, Cobo N, Bautista D, Cuesta-Muñoz AL, Fuentes E, Juan-Pico P, Castro MJ, Milman G, Mechoulam R, Nadal A, Rodríguez de Fonseca F.

Diabetologia. 2008 Mar;51(3):476-87. Epub 2007 Dec 19.

PMID: 18092149 [PubMed – indexed for MEDLINE]

Related Articles

RESULTS: Human islets of Langerhans [isolated groups of cells in the pancreas that make hormones that help the body break down and use food] expressed

CB1 and CB2 (also known as CNR1 and CNR2) mRNA and CB1 and CB2 proteins, and also the machinery involved in synthesis and degradation of 2-AG (the most abundant endocannabinoid, levels of which were modulated by glucose).

….. CB1 was densely located in glucagon-secreting alpha cells and less so in insulin-secreting beta cells.

…….CB2 was densely present in somatostatin-secreting delta cells, but absent in alpha and beta cells.

…. CB1 stimulation enhanced insulin and glucagon secretion, while

….CB2 agonism lowered glucose-dependent insulin secretion,

….showing these cannabinoid receptors to be functional.

CONCLUSIONS/INTERPRETATION: Together, these results suggest a role for endogenous endocannabinoid signalling in regulation of endocrine secretion in the human pancreas.

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See also:

Central versus peripheral antagonism of cannabinoid CB1 receptor in obesity: effects of LH-21, a peripherally acting neutral cannabinoid receptor antagonist, in Zucker rats.

Pavón FJ, Serrano A, Pérez-Valero V, Jagerovic N, Hernández-Folgado L, Bermúdez-Silva FJ, Macías M, Goya P, de Fonseca FR.

J Neuroendocrinol. 2008 May;20 Suppl 1:116-23. Review.

PMID: 18426510 [PubMed – indexed for MEDLINE]

Related Articles

Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPAR alpha ligands in mouse pancreatic islets of Langerhans.

Ropero AB, Juan-Picó P, Rafacho A, Fuentes E, Bermúdez-Silva FJ, Roche E, Quesada I, de Fonseca FR, Nadal A.

J Endocrinol. 2009 Feb;200(2):127-38. Epub 2008 Nov 18.

PMID: 19017711 [PubMed – in process]

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.

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

PMID: 18782018 [PubMed – indexed for MEDLINE]

Related Articles

Behavioral effects of CB2 cannabinoid receptor activation and its influence on food and alcohol consumption.

Onaivi ES, Carpio O, Ishiguro H, Schanz N, Uhl GR, Benno R.

Ann N Y Acad Sci. 2008 Oct;1139:426-33.

PMID: 18991890 [PubMed – indexed for MEDLINE]

Related Articles

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Wang & Ueda 2008

Curr Opin Nephrol Hypertens. 2008 Jan;17(1):1-10.

Links

Role of the endocannabinoid system in metabolic control.

Wang J, Ueda N.

Department of Biochemistry, Kagawa University School of Medicine, Kagawa, Japan.

Growing evidence suggests an important role in metabolic control of the endocannabinoid system, which is composed of cannabinoid receptors, endocannabinoids, and related enzymes. In this short review, we describe the latest advances in this research field, including the antiobesity effect of the cannabinoid receptor CB1 antagonist rimonabant and the anorexic effect of N-oleoylethanolamine, an endocannabinoid-related, endogenous substance. RECENT FINDINGS: CB1 is expressed not only in various brain regions, including hypothalamus, but also in peripheral organs such as adipose tissue and liver. The endocannabinoid system appears to function as a physiological system regulating food intake, energy balance, and lipid metabolism through both central and peripheral mechanisms.

Obesity

may be associated with hyperactivity of the endocannabinoid system.

Large phase III trials of rimonabant confirmed significant weight loss and waist circumference reduction in overweight and obese patients. The levels of HDL-cholesterol, triglycerides, and HbA1c were also improved. The anorexic effect of N-oleoylethanolamine was suggested to be mediated by peroxisome proliferator-activated receptor-alpha and the G protein-coupled receptor GPR119. SUMMARY: These results highlight the importance of an endocannabinoid tone in metabolic control and therapeutic usefulness of CB1 antagonists. Derivatives of N-oleoylethanolamine may be developed as new antiobesity drugs.

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See also:

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

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Di Marzo et al 2001b

Nature. 2001 Apr 12;410(6830):822-5.

Links

Comment in:

Nature. 2001 Apr 12;410(6830):763, 765.

Leptin-regulated endocannabinoids are involved in maintaining food intake.

Di Marzo V, Goparaju SK, Wang L, Liu J, Bátkai S, Járai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G.

Endocannabinoid Research Group, Istituto per la Chimica di Molecole di Interesse Biologico, CNR, 80072, Arco Felice, Naples, Italy.

Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake and energy balance.

Leptin reduces food intake by upregulating anorexigenic (appetite-reducing) neuropeptides, such as alpha-melanocyte-stimulating hormone, and downregulating orexigenic (appetite-stimulating) factors, primarily neuropeptide Y. Genetic defects in anorexigenic signaling, such as mutations in the melanocortin-4 (ref. 5) or leptin receptors, cause obesity. However, alternative orexigenic pathways maintain food intake in mice deficient in neuropeptide Y. CB1 cannabinoid receptors and the endocannabinoids anandamide and 2-arachidonoyl glycerol are present in the hypothalamus, and marijuana and anandamide stimulate food intake. Here we show that following temporary food restriction, CB1 receptor knockout mice eat less than their wild-type littermates, and the CB1 antagonist SR141716A reduces food intake in wild-type but not knockout mice. Furthermore, defective leptin signaling is associated with elevated hypothalamic, but not cerebellar, levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats.

Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus. These findings indicate that

endocannabinoids in the hypothalamus

may tonically activate CB1 receptors

to maintain food intake and

form part of the neural circuitry regulated by leptin.

See also:

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

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Maccioni et al 2008

Behav Pharmacol. 2008 May;19(3):197-209.Click here to read Links

Suppression by the cannabinoid CB1 receptor antagonist, rimonabant, of the reinforcing and motivational properties of a chocolate-flavoured beverage in rats.

Maccioni P, Pes D, Carai MA, Gessa GL, Colombo G.

CNR Institute of Neuroscience, Cagliari, Ital

Pharmacological blockade of the cannabinoid CB1 receptor has been repeatedly reported to suppress intake of food, including highly palatable foods, in laboratory animals.

……This study was designed to investigate whether treatment with the cannabinoid CB1 receptor antagonist, rimonabant, would reduce the reinforcing and motivational properties of a chocolate-flavoured … in nonfood-deprived and nonwater-deprived Wistar rats trained to self-administer this beverage under an operant conditioning procedure.

…..This study was also aimed at assessing to what degree self-administration behaviour could be manipulated environmentally

. …All rats rapidly acquired and steadily maintained high levels of self-administration of the chocolate-flavoured beverage. Changes in experimental conditions modified the rats’ self-administration behaviour; these changes seemed to be the result of the rats’ attempt to adjust their behaviour so as to consume as much of the chocolate-flavoured beverage as possible when it was presented at its most palatable 5% concentration.

…… Treatment with rimonabant dose-dependently suppressed self-administration of the chocolate-flavoured beverage. When rimonabant was administered repeatedly, only a modest degree of tolerance developed to its reducing effect. Finally, treatment with rimonabant resulted in a dose-dependent reduction of the motivational properties of the chocolate-flavoured beverage, measured by the progressive ratio schedule of reinforcement and extinction-responding procedure.

……These results suggest that self-administration of a chocolate-flavoured beverage can be rapidly and reliably established in rats and that this behaviour is environmentally manipulable.

……These results also suggest that the

…..cannabinoid CB1 receptor is a crucial component

…..of the neural substrate mediating the reinforcing and motivational properties of a highly palatable food such as a chocolate-flavoured beverage.

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See also:

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

J Clin Invest. 2005 May;115(5):1130-3.

Links

Comment on:

J Clin Invest. 2005 May;115(5):1298-305.

Food for thought: endocannabinoid modulation of lipogenesis.

Lichtman AH, Cravatt BF.

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, 23298, USA. alichtma@hsc.vcu.edu

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Di Blasio et al 2003

Clin Endocrinol (Oxf). 2003 Jul;59(1):68-74.

Links

The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients.

Di Blasio AM, van Rossum EF, Maestrini S, Berselli ME, Tagliaferri M, Podestà F, Koper JW, Liuzzi A, Lamberts SW.

Molecular Biology Laboratory, Ospedale San Giuseppe, Istituto Auxologico Italiano, Verbania, and Department of Food Science and Microbiology, University of Milano, Italy.

OBJECTIVE: We have recently reported that, in healthy elderly Dutch individuals, a N363S polymorphism in the glucocorticoid receptor (GR) gene is associated with

higher sensitivity to low-dose dexamethasone (0.25 mg),

evaluated as both cortisol suppression and insulin response,

and with an increased body mass index (BMI).

In the present study we investigated the role of the N363S polymorphism, and a BclI restriction site polymorphism in a group of Italian patients with severe obesity…..

….when we studied the effect of the presence of the BclI polymorphism and the N363S variant in the same individual, we found that the subjects who carried both polymorphisms had a tendency towards higher systolic and diastolic blood pressure and significantly higher total and LDL-cholesterol levels (P = 0.005 and P = 0.05, respectively). DISCUSSION: Taking the results of this study and those obtained in the Dutch population, we speculate that heterozygous carriers of the N363S variant who develop obesity, may become even more obese, possibly because they have a hypersensitive insulin response and thus,

via activation of lipogenesis, store fat more efficiently.

Furthermore, these data suggest that N363S carriers who carry the BclI polymorphism as well, tend to have a slightly unfavorable cardiovascular profile.

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Spoto et al 2006

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

Links

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.

CNR-IBIM, National Research Council Institute of Biomedicine-Clinical Epidemiology and Physiophatology of Renal Disease and Hypertension & Urology Unit, c/o Ki Point-Gransial Srl, Via Filippini, n.85, 89125 Reggio Calabria, Italy.

Endocannabinoids are a group of biologically active endogenous lipids that have

recently emerged as important mediators in energy balance control.

The two best studied endocannabinoids, anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) are the endogenous ligands of the central and peripheral cannabinoid receptors. …………Furthermore, AEA binds to the transient receptor potential vanilloid type-1 (TRPV1), a capsaicin-sensitive, non-selective cation channel.

…..The synthesis of these endocannabinoids is catalyzed by the N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and the sn-1-selective diacylglycerol lipase (DAGL),

….whereas their degradation is accomplished by the fatty acid amide hydrolase (FAAH) and the monoglyceride lipase (MGL), respectively.

We investigated the presence of a functional endocannabinoid system in human adipose tissue

……..from seven healthy subjects.

…….Subcutaneous abdominal adipose tissue underwent biochemical and molecular biology analyses, aimed at testing the expression of this system and its functional activity. AEA and 2-AG levels were detected and quantified by HPLC. Real time PCR analyzed the expression of the endocannabinoid system and immunofluorescence assays showed the distribution of its components in the adipose tissue.

……… Furthermore, binding assay for the cannabinoid and vanilloid receptors and activity assay for each metabolic enzyme of the endocannabinoid system gave clear evidence of a fully operating system.

………..The data presented herein show for the first time that the human adipose tissue is able to bind AEA and 2-AG and that it is endowed with the biochemical machinery to metabolize endocannabinoids.

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Cota 2008b

Front Horm Res. 2008;36:135-45.

Links

Role of the endocannabinoid system in energy balance regulation and obesity.

Cota D.

Department of Psychiatry, University of Cincinnati, Cincinnati, OH 45237, USA. daniela.cota@uc.edu

The endogenous cannabinoid system (ECS) is a neuromodulatory system recently recognized to have a role in the regulation of various aspects of eating behavior and energy balance through central and peripheral mechanisms.

In the central nervous system, cannabinoid type 1 receptors and their endogenous ligands, the endocannabinoids, are involved in modulating food intake and motivation to consume palatable food.

Moreover, the ECS is present in peripheral organs, such as

liver,

white adipose tissue,

muscle, and

pancreas,

where it seems to be involved in the regulation of lipid and glucose homeostasis.

Dysregulation of the ECS has been associated with the development of obesity and its sequelae, such as dyslipidemia and diabetes. Conversely, recent clinical trials have shown that cannabinoid type 1 receptor blockade may ameliorate these metabolic abnormalities. Although further investigation is needed to better define the actual mechanisms of action, pharmacologic approaches targeting the ECS may provide a novel, effective option for the management of obesity, type 2 diabetes and cardiovascular disease.

See also:

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

Cota D.

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

PMID: 18426497 [PubMed – indexed for MEDLINE]

Related Articles

CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular health.

Cota D.

Diabetes Metab Res Rev. 2007 Oct;23(7):507-17. Review.

PMID: 17683024 [PubMed – indexed for MEDLINE]

Related Articles

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.

Endocrinology. 2007 Apr;148(4):1574-81. Epub 2006 Dec 28.

PMID: 17194743 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

The emerging role of the endocannabinoid system in endocrine regulation and energy balance.

Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R.

Endocr Rev. 2006 Feb;27(1):73-100. Epub 2005 Nov 23. Review.

PMID: 16306385 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis.

Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thöne-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst AC, Pasquali R, Lutz B, Stalla GK, Pagotto U.

J Clin Invest. 2003 Aug;112(3):423-31.

PMID: 12897210 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

Endogenous cannabinoid system as a modulator of food intake.

Cota D, Marsicano G, Lutz B, Vicennati V, Stalla GK, Pasquali R, Pagotto U.

Int J Obes Relat Metab Disord. 2003 Mar;27(3):289-301. Review.

PMID: 12629555 [PubMed – indexed for MEDLINE]

Related Articles
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Spoto et al 2006b

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

Links

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.

CNR-IBIM, National Research Council Institute of Biomedicine-Clinical Epidemiology and Physiophatology of Renal Disease and Hypertension & Urology Unit, c/o Ki Point-Gransial Srl, Via Filippini, n.85, 89125 Reggio Calabria, Italy.

Endocannabinoids are a group of biologically active

endogenous lipids that have recently emerged as

important mediators in energy balance control.

The two best studied endocannabinoids,

….anandamide (N-arachidonoylethanolamine, AEA) and

…..2-arachidonoylglycerol (2-AG) are the endogenous ligands of the central and peripheral cannabinoid receptors.

Furthermore, AEA binds to the transient receptor potential vanilloid type-1 (TRPV1), a capsaicin [an ingredient in hot peppers that can be found in ointment form for use on the skin to relieve pain from diabetic neuropathy; capsaicin n. A colorless, pungent, crystalline compound, C 18 H 27 NO 3 , that is derived from capsicum and is a strong irritant to skin and mucous] -sensitive, non-selective cation [an atom or group of atoms with a positive charge] channel.

The synthesis of these endocannabinoids

…..is catalyzed by the N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) …..and the sn-1-selective diacylglycerol lipase (DAGL),

…..whereas their degradation is accomplished by the fatty acid amide hydrolase (FAAH)

……and the monoglyceride lipase (MGL), respectively. [AEA and 2-AG?]

We investigated the presence of a functional endocannabinoid system in human adipose tissue from seven healthy subjects….binding assay for the cannabinoid and vanilloid receptors and activity assay for each metabolic enzyme of the endocannabinoid system gave clear evidence of a fully operating system.

The data presented herein show for the first time that the human adipose tissue is able to bind AEA and 2-AG and that it is endowed with the biochemical machinery to metabolize endocannabinoids.

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Fegley et al 2004

Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8756-61. Epub 2004 May 11.

Links

Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172.

Fegley D, Kathuria S, Mercier R, Li C, Goutopoulos A, Makriyannis A, Piomelli D.

Department of Pharmacology and Center for the Neurobiology of Learning and Memory, University of California, Irvine, CA 92697-4625, USA.

The endogenous cannabinoid anandamide

….is removed from the synaptic space

…..by a high-affinity transport system present in neurons and astrocytes,

…..which is inhibited by N-(4-hydroxyphenyl)-arachidonamide (AM404).

After internalization, anandamide is hydrolyzed by fatty-acid amide hydrolase (FAAH),

…..an intracellular membrane-bound enzyme that also cleaves AM404.

Based on kinetic evidence, it has recently been suggested that

….anandamide internalization may be mediated by passive diffusion driven by FAAH activity.

The results indicate that anandamide internalization in mouse brain neurons is independent of FAAH activity. In further support of this conclusion, the compound N-(5Z, 8Z, 11Z, 14Z eicosatetraenyl)-4-hydroxybenzamide (AM1172) blocked [(3)H]anandamide internalization in rodent cortical neurons and human astrocytoma cells without acting as a FAAH substrate or inhibitor. AM1172 may serve as a prototype for novel anandamide transport inhibitors with increased metabolic stability.

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Bermúdez-Siva et al 2006

Eur J Pharmacol. 2006 Feb 15;531(1-3):282-4. Epub 2006 Jan 19.

Links

Activation of cannabinoid CB1 receptors induces glucose intolerance in rats.

Bermúdez-Siva FJ, Serrano A, Diaz-Molina FJ, Sánchez Vera I, Juan-Pico P, Nadal A, Fuentes E, Rodríguez de Fonseca F.

Fundación IMABIS, Hospital Carlos Haya, Avenida Carlos Haya s/n, 7(a) Planta, Pabellón A, Málaga 29010, Spain. franciscoj.bermudez.exts@juntadeandalucia.es

Recent reports have described the presence of cannabinoid CB1 receptors in pancreatic islets. Here we show that administration of the endogenous cannabinoid anandamide or the selective cannabinoid CB1 receptor agonist Arachidonyl-2′-chloroethylamide (ACEA) results in glucose intolerance after a glucose load. This effect is reversed by the selective cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251). These results suggest that targeting cannabinoid CB1 receptors may serve as new therapeutic alternatives for metabolic disorders such as diabetes.

See also:

Cannabinoid receptors regulate Ca(2+) signals and insulin secretion in pancreatic beta-cell.

Juan-Picó P, Fuentes E, Bermúdez-Silva FJ, Javier Díaz-Molina F, Ripoll C, Rodríguez de Fonseca F, Nadal A.

Cell Calcium. 2006 Feb;39(2):155-62.

PMID: 16321437 [PubMed – indexed for MEDLINE]

Related Articles

Phytother Res. 2009 May 13. [Epub ahead of print]

Links

Beneficial effects of a Cannabis sativa extract treatment on diabetes-induced neuropathy and oxidative stress.

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

Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.

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DIABETES

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Curr Opin Clin Nutr Metab Care. 2008 Jul;11(4):505-11.

Links

Inhibitors of cannabinoid receptors and glucose metabolism.

Scheen AJ, Paquot N.

Division of Diabetes, Nutrition and Metabolic Disorders, CHU Sart Tilman, University of Liège, Liège, Belgium. andre.scheen@chu.ulg.ac.be

Crit Pathw Cardiol. 2007 Jun;6(2):46-50.

Links

The endocannabinoid system: a new target for the regulation of energy balance and metabolism.

Després JP.

Québec Heart Institute, Québec QC, Canada. jean-pierre.despres@crhl.ulaval.ca

Vnitr Lek. 2006 Jun;52(6):615-8.

Links

[Impact of endocannabinoid system in modulation of cardiometabolic risk factors]

[Article in Czech]

Sulcová A.

Farmakologický ustav Lékarské fakulty MU, Brno. sulcova@med.muni.cz

Curr Protein Pept Sci. 2009 Feb;10(1):56-74.

Links

The endocannabinoid system: a promising target for the management of type 2 diabetes.

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

Best Pract Res Clin Endocrinol Metab. 2007 Dec;21(4):535-53.

Links

Cannabinoid-1 receptor antagonists in type-2 diabetes.

Scheen AJ.

Division of Diabetes, Nutrition and Metabolic Disorders, CHU Sart Tilman (B35), University of Liege, B 4000 Liege, Belgium. andre.scheen@chu.ulg.be

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.

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Matsuda et al 2005

Abstract – Japan

AIMS/HYPOTHESIS: We examined the presence of functional cannabinoid receptors 1 and 2 (CB1, CB2) in isolated human islets, phenotyped the cells producing cannabinoid receptors and analysed the actions of selective cannabinoid receptor agonists on insulin, glucagon and somatostatin secretion in vitro.

RESULTS: Human islets of Langerhans expressed CB1 and CB2 (also known as CNR1 and CNR2) mRNA and CB1 and CB2 proteins, and also the machinery involved in synthesis and degradation of 2-AG (the most abundant endocannabinoid, levels of which were modulated by glucose).

… CB1 was densely located in glucagon-secreting alpha cells and less so in insulin-secreting beta cells.

…..CB2 was densely present in somatostatin-secreting delta cells, but absent in alpha and beta cells.

….. CB1 stimulation enhanced insulin and glucagon secretion, while CB2 agonism lowered glucose-dependent insulin secretion, showing these cannabinoid receptors to be functional. CONCLUSIONS/INTERPRETATION: Together, these results suggest a role for endogenous endocannabinoid signalling in regulation of endocrine secretion in the human pancreas.

See also:

The cannabinoid 1 receptor antagonist, AM251, prolongs the survival of rats with severe acute pancreatitis.

Matsuda K, Mikami Y, Takeda K, Fukuyama S, Egawa S, Sunamura M, Maruyama I, Matsuno S.

Tohoku J Exp Med. 2005 Oct;207(2):99-107.

PMID: 16141678 [PubMed – indexed for MEDLINE]

Related Articles Free article at journal site

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Dembiński et al 2006

Abstract – Poland

Recent studies have shown that stimulation of cannabinoid 1 (CB1) receptoraffects activity of the digestive tract.

The aim of the present study was to check whether the administration of CB1 receptor agonist or antagonist affects the stress-induced gastric ulceration and development of edematous pancreatitis. …

RESULTS: Administration of anandamide reduced gastric lesions and this effect was associated with an increase in gastric mucosal blood flow and mucosal DNA synthesis; whereas serum level of pro-inflammatory interleukin-1 beta was reduced. Treatment with AM 251 aggravated gastric damage and reversed protective effect of anandamide administration. Opposite effect was observed in the pancreas. Administration of anandamide increased dose-dependently the severity of pancreatitis.

CONCLUSIONS: Activation of CB1 receptors evokes

…..opposite effects in the stomach and pancreas:

…..in the stomach, exhibits protective effect against stress-induced gastric mucosal lesions;

…..whereas in the pancreas, increases the severity of cerulein-induced pancreatitis.

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

Mule et al 2007

Pharmacol Res. 2007 Sep;56(3):185-92. Epub 2007 Jun 21.

Links

Involvement of CB1 and CB2 receptors in the modulation of cholinergic neurotransmission in mouse gastric preparations.

Mulè F, Amato A, Baldassano S, Serio R.

Dipartimento di Biologia cellulare e dello Sviluppo, Viale delle Scienze, Università di Palermo, 90128 Palermo, Italy. fmule@unipa.it

While most of the studies concerning the

role of cannabinoids on gastric motility

have focused the attention on the gastric emptying in in vivo animal models, there is little information about the cannabinoid peripheral influence in the stomach.

…….. In addition, the functional features of CB2 receptors in the gastrointestinal tract have been poorly characterized. The purpose of the present study

…..was to investigate the effects of cannabinoid drugs on the excitatory cholinergic and inhibitory non-adrenergic non-cholinergic (NANC) neurotransmission in mouse isolated gastric preparations.

In conclusion, the present results suggest that cannabinoids

….play a prejunctional modulatory role on the cholinergic excitatory transmission

…..without affecting the NANC inhibitory transmission.

…..In addition, this study provides experimental evidence that also the activation of CB2 receptors is able to reduce cholinergic neurotransmission in the mouse stomach.

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

Gut. 2001 Jun;48(6):859-67.

Links

Cannabinoids and the gastrointestinal tract.

Pertwee RG.

Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen Foresterhill, Aberdeen AB25 2ZD, UK. rgp@aberdeen.ac.uk

Eur Rev Med Pharmacol Sci. 2008 Aug;12 Suppl 1:81-93.

Links

Cannabinoids and gastrointestinal motility: animal and human studies.

Aviello G, Romano B, Izzo AA.

Department of Experimental Pharmacology and Endocannabinoid Research Group, University of Naples Federico II, Naples, Ital

Prostaglandins Leukot Essent Fatty Acids. 2002 Feb-Mar;66(2-3):333-41.

Links

Endocannabinoids and the gut.

Pinto L, Capasso R, Di Carlo G, Izzo AA.

Department of Experimental Pharmacology, University of Naples Federico II, via D. Montesano 49, 80131 Naples, Italy.

Br J Pharmacol. 2007 Nov;152(5):663-70. Epub 2007 Sep 3.

Links

Endocannabinoids and the gastrointestinal tract: what are the key questions?

Sanger GJ.

Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Limited, New Frontiers Science Park, Harlow, UK. Gareth.J.Sanger@gsk.com

J Mol Med. 2005 Dec;83(12):944-54. Epub 2005 Aug 26.

Links

The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract.

Massa F, Storr M, Lutz B.

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

Clin Exp Pharmacol Physiol. 2008 Nov;35(11):1383-7. Epub 2008 Jul 29.

Links

Gastrointestinal endocannabinoid system: multifaceted roles in the healthy and inflamed intestine.

Smid SD.

Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia. scott.smid@adelaide.edu.au

++++++++

Curr Opin Pharmacol. 2001 Dec;1(6):597-603.

Links

The gastrointestinal pharmacology of cannabinoids.

Izzo AA, Mascolo N, Capasso F.

Department of Experimental Pharmacology, University of Naples Federico II, Italy. aaizzo@unina.it

The digestive tract contains endogenous cannabinoids (anandamide and 2-arachidonylglycerol) and cannabinoid CB1 receptors can be found on myenteric and submucosal nerves. Activation of CB1 receptors inhibits gastrointestinal motility, intestinal secretion and gastric acid secretion. The enteric location of CB1 receptors could provide new strategies for the management of gut disorders.

++++++

Izzo 2007

Mammalian tissues express the cannabinoid 1 (CB(1)) receptor and the cannabinoid 2 (CB(2)) receptor, the latter being involved in inflammation and pain. In somatic nerve pathways, the analgesic effects of CB(2) agonism are well documented. Two papers published in the Journal have provided evidence that CB(2) receptor activation inhibits visceral afferent nerve activity in rodents. These exciting findings are discussed in the context of recent data highlighting the emerging role of CB(2) receptor as a critical target able to counteract hypermotility in pathophysiological states, gut inflammation and possibly colon cancer.

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

Duncan, Davison & Sharkey 2005

Aliment Pharmacol Ther. 2005 Oct 15;22(8):667-83.

Links

Review article: endocannabinoids and their receptors in the enteric nervous system.

Duncan M, Davison JS, Sharkey KA.

Institute for Infection, Immunity and Inflammation and Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, AB, Canada.

The therapeutic actions of cannabinoids have been known for centuries. In the last 25 years this area of research has grown exponentially with the discovery of specific cannabinoid receptors and endogenous ligands. In the enteric [small intestine] nervous system of gastrointestinal tract, cannabinoid receptors are located on enteric nerve terminals where they exert inhibitory actions on neurotransmission to reduce motility and secretion.

Endogenous cannabinoids are present in the enteric nervous system, as are the degradative enzymes necessary to inhibit their action. The cellular mechanism of action of endocannabinoids has not been established in the enteric nervous system.

Endocannabinoids not only act at cannabinoid receptors,

but potentially also at

vanilloid and

*********5-HT3 receptors+++++++

[see Xiong et al 2008]

both of which are expressed in the gastrointestinal tract. The interactions between endocannabinoids and these other important receptor systems have not been extensively investigated. A greater understanding of the endocannabinoid system in the enteric nervous system could lead to advances with important therapeutic potential in the treatment of gastrointestinal disorders such as irritable bowel syndrome, inflammatory bowel disease, secretory diarrhoea and gastro-oesophageal reflux disease.

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Massa & Monory 2006

J Endocrinol Invest. 2006;29(3 Suppl):47-57.

Links

Endocannabinoids and the gastrointestinal tract.

Massa F, Monory K.

Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, 55099 Mainz, Germany. massa@uni-mainz.de

In the past centuries, different preparations of marijuana have been used for the treatment of gastrointestinal (GI) disorders, such as GI pain, gastroenteritis and diarrhea. Delta9-tetrahydrocannabinol (THC; the active component of marijuana), as well as endogenous and synthetic cannabinoids, exert their biological functions on the gastrointestinal tract by activating two types of cannabinoid receptors, cannabinoid type 1 receptor (CB1 receptor) and cannabinoid type 2 receptor (CB2 receptor).

While

CB1

receptors are located in the enteric nervous system and in sensory terminals of vagal and spinal neurons and

regulate neurotransmitter release,

CB2

receptors are mostly distributed in the immune system,

with a role presently still difficult to establish.

Under pathophysiological conditions, the endocannabinoid system conveys protection to the GI tract, eg from inflammation and abnormally high gastric and enteric secretion. For such protective activities, the endocannabinoid system may represent a new promising therapeutic target against different GI disorders, including frankly inflammatory bowel diseases (eg, Crohn’s disease), functional bowel diseases (eg, irritable bowel syndrome), and secretion- and motility-related disorders.

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Wright, Duncan & Sharkey 2008

Br J Pharmacol. 2008 Jan;153(2):263-70. Epub 2007 Oct 1.

Links

Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation.

Wright KL, Duncan M, Sharkey KA.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK

.

The emerging potential for the cannabinoid (CB) system in modulating gastrointestinal inflammation has gained momentum over the last few years. Traditional and anecdotal use of marijuana for gastrointestinal disorders, such as diarrhoea and abdominal cramps is recognized, but the

therapeutic benefit of cannabinoids in the 21st century is overshadowed by the psychoactive problems associated with CB1 receptor activation.

CB2 activation is not related to psychoactive complaint

However, the presence and function of the CB2 receptor in the GI tract, whilst not yet well characterized, holds great promise due to its immunomodulatory roles in inflammatory systems and its lack of psychotropic effects. This review of our current knowledge of CB2 receptors in the gastrointestinal tract highlights its role in regulating abnormal motility, modulating intestinal inflammation and limiting visceral sensitivity and pain.

CB2 receptors represent a braking system and a

pathophysiological mechanism for the

resolution of inflammation and many of its symptoms.

CB2 receptor activation therefore represents a very promising therapeutic target in gastrointestinal inflammatory states where there is immune activation and motility dysfunction.

++++

Wright et al 2005

Gastroenterology. 2005 Aug;129(2):437-53.

Links

Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing.

Wright K, Rooney N, Feeney M, Tate J, Robertson D, Welham M, Ward S.

Department of Pharmacy and Pharmacology, University of Bath, UK. K.L.Wright@bath.ac.uk

BACKGROUND & AIMS: Two G-protein-coupled cannabinoid receptors, termed CB1 and CB2, have been identified and several mammalian enteric nervous systems express CB1 receptors and produce endocannabinoids.

An immunomodulatory role for the endocannabinoid system in gastrointestinal inflammatory disorders has been proposed and this study sought to determine the location of both cannabinoid receptors in human colon and to investigate epithelial receptor function. METHODS: The location of CB1 and CB2 receptors in human colonic tissue was determined by immunohistochemistry. Primary colonic epithelial cells were treated with both synthetic and endogenous cannabinoids in vitro, and biochemical coupling of the receptors to known signaling events was determined by immunoblotting. Human colonic epithelial cell lines were used in cannabinoid-binding studies and as a model for in vitro wound-healing experiments. RESULTS: CB1-receptor immunoreactivity was evident in normal colonic epithelium, smooth muscle, and the submucosal myenteric plexus. CB1- and CB2-receptor expression was present on plasma cells in the lamina propria, whereas only CB2 was present on macrophages. CB2 immunoreactivity was seen in the epithelium of colonic tissue characteristic of inflammatory bowel disease.

Cannabinoids enhanced epithelial wound closure either alone or in combination

with lysophosphatidic acid through a CB1-lysophosphatidic acid 1 heteromeric receptor complex.

CONCLUSIONS: CB1 receptors are expressed in normal human colon and colonic epithelium is responsive biochemically and functionally to cannabinoids. Increased epithelial CB2-receptor expression in human inflammatory bowel disease tissue implies an immunomodulatory role that may impact on mucosal immunity.

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