Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anandamide (arachidonylethanolamide), isolated from the porcine brain, and 2-arachidonyl-glycerol (2-Ara-Gl), derived from the canine gut, are two recently identified putative endogenous cannabinoid receptor ligands. Both ligands have been reported to possess binding affinity for cannabinoid receptor subtypes, CB1 and CB2. The objective of the present studies was to investigate the immunomodulatory effects of both of these ligands in B6C3F1 mouse splenocytes. 2-Ara-Gl produced a marked and dose-related inhibition of the mixed lymphocyte response, anti-CD3 mAb-induced T-cell proliferation and LPS-induced B-cell proliferation, whereas having no inhibitory effect on phorbol-12-myristate-13-acetate/ionomycin-induced cell proliferation. Interestingly, the inhibitory effects by 2-Ara-Gl on proliferation were at least dependent in part on cell density. At high cell density, 2-Ara-Gl enhanced lymphoproliferation whereas exhibiting marked inhibitory activity at low cell density. Similarly, in vitro primary immunoglobulin M antibody-forming cell responses which are dependent on high cell density also were found to be enhanced by 2-Ara-Gl. Conversely, anandamide exhibited no inhibitory effects on cell proliferative responses to stimulation by anti-CD3 mAb, lipopolysaccharide or phorbol-12-myristate-13-acetate/ionomycin treatment. Anandamide also showed no effect on the in vitro sheep erythrocyte antibody-forming cell response. Although shown previously to markedly inhibit forskolin-stimulated cyclic AMP accumulation, 2-Ara-Gl exhibited no effect on basal adenylate cyclase activity in splenocytes. Additionally, anandamide showed negligible inhibitory effects at extremely high concentrations on forskolin-stimulated adenylate cyclase activity and no effect on basal adenylate cyclase activity in splenocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of putative cannabinoid receptor ligands, anandamide and 2-arachidonyl-glycerol, on immune function in B6C3F1 mouse splenocytes. 747 35

Arachidonic acid ethanolamide (anandamide) is a brain constituent that binds to the brain cannabinoid receptor (CB1). It produces many of the pharmacological effects caused by delta 9-tetrahydrocannabinol (delta 9-THC) in mice. Anandamide parallels delta 9-THC in its specific interaction with the cannabinoid receptor and in inhibition of adenylate cyclase. Two additional fatty acid ethanolamides that bind to the cannabinoid receptor, homo-gamma-linolenylethanolamide and docostetraenylethanolamide, have been identified in the brain. We believe that the anandamides are involved in the coordination of movement and short term memory. Depression of ambulation in an open field and the analgetic response to anandamide are not fully developed until adulthood, possibly due to an age-related increase in the CB1 receptor concentration. This observation has clinical implications in pediatrics. A second cannabinoid receptor (CB2) is present in the spleen. A monoglyceride, 2-arachidonyl-glycerol which binds to both CB1 and CB2 in transfected cells and inhibits andenylate cyclase in spleen cells was found in the gut. Its role is apparently associated with the immune system. These fatty acids amides and esters represent a new family of chemical modulators in the body.
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PMID:Endogenous cannabinoid ligands--chemical and biological studies. 890 44

2-Arachidonoylglycerol (2-AG) is a unique molecular species of monoacylglycerol isolated from rat brain and canine gut as an endogenous cannabinoid receptor ligand (Sugiura, T., Kondo, S., Sukagawa, A., Nakane, S., Shinoda, A., Itoh, K., Yamashita, A., Waku, K., 1995. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89-97; Mechoulam, R., Ben-Shabat, S., Hanus, L., Ligumsky, M., Kaminski, N. E., Schatz, A.R., Gopher, A., Almog, S., Martin, B.R., Compton, D.R., Pertwee, R.G., Giffin, G., Bayewitch, M., Brag, J., Vogel, Z., 1995. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83-90). 2-AG binds to the cannabinoid receptors (CB1 and CB2) and exhibits a variety of cannabimimetic activities in vitro and in vivo. Recently, we found that 2-AG induces Ca(2+) transients in NG108-15 cells, which express the CB1 receptor, and in HL-60 cells, which express the CB2 receptor, through a cannabinoid receptor- and Gi/Go-dependent mechanism. Based on the results of structure-activity relationship experiments, we concluded that 2-AG but not anandamide is the natural ligand for both the CB1 and the CB2 receptors and both receptors are primarily 2-AG receptors. Evidences are gradually accumulating that 2-AG is a physiologically essential molecule, although further detailed studies appear to be necessary to determine relative importance of 2-AG and anandamide in various animal tissues. In this review, we described mainly our previous and current experimental results, as well as those of others, concerning the tissue levels, bioactions and metabolism of 2-AG.
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PMID:2-Arachidonoylglycerol and the cannabinoid receptors. 1110 84

1. We have studied the effect of cannabinoid agonists (CP 55,940 and cannabinol) on intestinal motility in a model of intestinal inflammation (induced by oral croton oil in mice) and measured cannabinoid receptor expression, endocannabinoids (anandamide and 2-arachidonylglycerol) and anandamide amidohydrolase activity both in physiological and pathophysiological states. 2. CP 55,940 (0.03 - 10 nmol mouse(-1)) and cannabinol (10 - 3000 nmol mouse(-1)) were more active in delaying intestinal motility in croton oil-treated mice than in control mice. These inhibitory effects were counteracted by the selective cannabinoid CB(1) receptor antagonist SR141716A (16 nmol mouse(-1)). SR141716A (1 - 300 nmol mouse(-1)), administered alone, increased intestinal motility to the same extent in both control and croton oil-treated mice. 3. Croton oil-induced intestinal inflammation was associated with an increased expression of CB(1) receptor, an unprecedented example of up-regulation of cannabinoid receptors during inflammation. 4. High levels of anandamide and 2-arachidonylglycerol were detected in the small intestine, although no differences were observed between control and croton oil-treated mice; by contrast anandamide amidohydrolase activity increased 2 fold in the inflamed small intestine. 5. It is concluded that inflammation of the gut increases the potency of cannabinoid agonists possibly by 'up-regulating' CB(1) receptor expression; in addition, endocannabinoids, whose turnover is increased in inflamed gut, might tonically inhibit intestinal motility.
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PMID:Cannabinoid CB1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. 1158 10

Delta9-Tetrahydrocannabinol, a major psychoactive component of marijuana, has been shown to interact with specific cannabinoid receptors, thereby eliciting a variety of pharmacological responses in experimental animals and human. In 1990, the gene encoding a cannabinoid receptor (CB1) was cloned. This prompted the search for endogenous ligands. In 1992, N-arachidonoylethanolamine (anandamide) was isolated from pig brain as an endogenous ligand, and in 1995, 2-arachidonoylglycerol was isolated from rat brain and canine gut as another endogenous ligand. Both anandamide and 2-arachidonoylglycerol exhibit various cannabimimetic activities. The results of structure-activity relationship experiments, however, revealed that 2-arachidonoylglycerol, but not anandamide, is the intrinsic natural ligand for the cannabinoid receptor. 2-Arachidonoylglycerol is a degradation product of inositol phospholipids that links the function of cannabinoid receptors with the enhanced inositol phospholipid turnover in stimulated tissues and cells. The possible physiological roles of cannabinoid receptors and 2-arachidonoylglycerol in various mammalian tissues such as those of the nervous system are discussed.
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PMID:Cannabinoid receptors and their endogenous ligands. 1209 54

Delta9-tetrahydrocannabinol (delta9-THC) is an effective anti-emetic; however, other potential gastrointestinal therapeutic effects of delta9-THC are less well-known. Here, we report a role of delta9-THC in a vago-vagal reflex that can result in gastro-oesophageal reflux, that is, gastric distension-evoked lower oesophageal sphincter (LOS) relaxation. Oesophageal, LOS and gastric pressures were measured using a miniaturized, manometric assembly in decerebrate, unanaesthetized ferrets.Gastric distension (30 ml) evoked LOS relaxation (70 +/- 8% decrease from baseline). Delta9-THC administered systemically (0.2 mg kg-1, iv.) or directly to the dorsal hindbrain surface (0.002 mg),significantly attenuated the nadir of the gastric distention-evoked LOS relaxation, and time to reach maximal response. Similar increases to maximal effect were observed after treatment with the cannabinoid receptor agonist WIN 55,212-2 (0.2 mg kg-1 iv.). The effect of systemic delta9-THC on gastric distention-evoked LOS relaxation was reversed by a selective cannabinoid1 (CBI) receptor antagonist, SR141617A (1 mg kg-1 i.v.). Since this reflex is vagally mediated, we used a CB1 receptor antiserum and immunocytochemistry to determine its distribution in ferret vagal circuitry. CBI receptor staining was present in cell bodies within the area postrema, nucleus tractus solitarius (NTS) and nodose ganglion. Intense terminal-like staining was noted within the NTS and dorsal motor vagal nucleus (DMN). Neither nodose ganglionectomy nor vagotomy altered the CB1 receptor terminal-like staining in the dorsal vagal complex. Retrogradely labelled gastric- or LOS-projecting DMN neurones did not express CBI receptors within their soma. Therefore, CBI receptor staining in the NTS and DMN is not due to primary vagal afferents or preganglionic neurones. These novel findings suggest that delta9-THC can modulate reflex LOS function and that the most likely site of action is via the CBI receptor within the NTS. This effect of delta9-THC may have implications in treatment of gastro-oesophageal reflux and other upper gut disorders.
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PMID:Cannabinoid1 receptor in the dorsal vagal complex modulates lower oesophageal sphincter relaxation in ferrets. 1287 65

Obesity is a major health problem and as a result, it is reasonable to consider pharmacological approaches alongside approaches involving diet, physical activity and lifestyle change. The currently available drugs, sibutramine and orlistat, result in modest, clinically worthwhile weight loss, with demonstrable improvements in co-morbidity, but do not meet the often unrealistic expectations of patients or health care professionals managing obese patients. There is insufficient data on efficacy or safety of other agents to support their use. Many new pharmacological approaches are under investigation. These include gut hormones, such a peptide YY (3-36) and cholecystokinin that normally signal satiety, and centrally-acting agents such as serotonin agonists, the anticonvulsants topiramate and zonisamide, cannabinoid receptor antagonists and drugs that act on other peptide neurotransmitter systems such as NPY and the melanocortins. Given the multiple pathways that influence energy balance, it is likely that therapies targeting more than one control system may be required in the future to meet the expectations and needs of patients needing to lose weight for medical reasons.
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PMID:Clinical evaluation of anti-obesity drugs. 1505 16

From a historical perspective to the present day, all the evidence suggests that activation of cannabinoid receptors (CBRs) is beneficial for gut discomfort and pain, which are symptoms related to dysmotility and visceral perception. CBRs comprise G-protein coupled receptors that are predominantly in enteric and central neurones (CB1R) and immune cells (CB2R). In the last decade, evidence obtained from the use of selective agonists and inverse agonists/antagonists indicates that manipulation of CB1R can alter (1) sensory processing from the gut, (2) brain integration of brain-gut axis, (3) extrinsic control of the gut and (4) intrinsic control by the enteric nervous system. The extent to which activation of CB1R is most critical at these different levels is related to the region of the GI tract. The upper GI tract is strongly influenced by CB1R activation on central vagal pathways, whereas intestinal peristalsis can be modified by CB1R activation in the absence of extrinsic input. Actions at multiple levels make the CB1R a target for the treatment of functional bowel disorders, such as IBS. Since low-grade inflammation may act as a trigger for occurrence of IBS, CB2R modulation could be beneficial, but there is little supporting evidence for this yet. The challenge is to accomplish CBR activation while minimizing adverse effects and abuse liabilities. Potential therapeutic strategies involve increasing signaling by endocannabinoids (EC). The pathways involved in the biosynthesis, uptake and degradation of EC provide opportunities for modulation of CB1R and some recent evidence with inhibitors of EC uptake and metabolism suggest that these could be exploited for therapeutic gain.
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PMID:Involvement of cannabinoid receptors in gut motility and visceral perception. 1510 Jan 66

Marijuana has been used as a traditional medicine and a pleasure-inducing drug for thousands of years around the world, especially in Asia. Delta(9)-tetrahydrocannabinol, major psychoactive component of marijuana, has been shown to interact with specific cannabinoid receptors, thereby eliciting a variety of pharmacological responses in experimental animals and human. In 1990, the gene encoding a cannabinoid receptor (CB1) was cloned. This prompted the search for endogenous ligands. In 1992, N-arachidonoylethanolamine (anandamide) was isolated from pig brain as an endogenous ligand, and in 1995, 2-arachidonoylglycerol was isolated from rat brain and canine gut as another endogenous ligand. Both anandamide and 2-arachidonoylglycerol exhibit various cannabimimetic activities. The results of structure-activity relationship experiments, however, revealed that 2-arachidonoylglycerol, but not anandamide, is the intrinsic natural ligand for the cannabinoid receptor. 2-arachidonoylglycerol is a degradation product of inositol phospholipids that links the function of the cannabinoid receptors with the enhanced inositol phospholipid turnover in stimulated tissues and cells. The possible physiological roles of cannabinoid receptors and 2-arachidonoylglycerol in various mammalian tissues such as those of the nervous and inflammatory cells are demonstrated. Furthermore, the future development of therapeutic drugs coming from this endocannabinoid system are discussed.
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PMID:[Endogenous cannabinoid receptor ligands--anandamide and 2-arachidonoylglycerol]. 1646 96

There is a widespread epidemic of obesity in the United States, which has been associated with an increased risk of diabetes mellitus, cancer, and cardiovascular diseases. Although lifestyle modifications and long-term dietary vigilance remain cornerstones of weight reduction treatment, the continued availability of U.S. Food and Drug Administration-approved pharmacotherapies has expanded the options available for the management of obesity. These agents include anorexiants, thermogenic drugs, and lipid-partitioning drugs. As knowledge regarding the possible causes of obesity increases, there are new drugs under investigation, which include beta3-adrenergic receptor agonists, modifiers of leptin, and cannabinoid receptor-1 antagonists (rimonabant). Also under investigation are antidiabetic agents (metformin, exenatide), anticonvulsant drugs (topiramate, zonisamide), antidepressants (bupropion, fluoxetine), and growth hormones. New targets for pharmacotherapy include uncoupling proteins, fatty acid synthase, neuropeptide Y, melanocortin, ghrelin, various regulatory gut peptides, and ciliary neurotropic factor. Pharmacologic agents are in clinical development that target these substances.
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PMID:Obesity: new perspectives and pharmacotherapies. 1692 65


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