|
| ||
|
|
||
Cannabinoid CB1 (cannabinoid + cb1)
Terms modified by Cannabinoid CB1 Selected AbstractsAugmentation of endogenous cannabinoid tone modulates lipopolysaccharide-induced alterations in circulating cytokine levels in ratsIMMUNOLOGY, Issue 2 2008Michelle Roche Summary The endogenous cannabinoid system plays an important role in regulating the immune system. Modulation of endogenous cannabinoids represents an attractive alternative for the treatment of inflammatory disorders. This study investigated the effects of URB597, a selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme catalysing degradation of the endogenous cannabinoid anandamide, and AM404, an inhibitor of anandamide transport, on lipopolysaccharide (LPS)-induced increases in plasma cytokine levels in rats. Both URB597 and AM404 potentiated the LPS-induced increase in plasma tumour necrosis factor-, (TNF-,) levels. The peroxisome proliferator-activated receptor , (PPAR,) antagonist, GW9662, attenuated the AM404-induced augmentation of TNF-, levels. Furthermore, the selective cannabinoid CB1 and CB2 receptor antagonists, AM251 and AM630 respectively, and the transient receptor potential vanilloid receptor-1 (TRPV1) antagonist, SB366791, reduced LPS-induced TNF-, plasma levels both alone and in combination with AM404. In contrast, AM404 inhibited LPS-induced increases in circulating interleukin-1, (IL-1,) and IL-6. AM251 attenuated the immunosuppressive effect of AM404 on IL-1,. None of the antagonists altered the effect of AM404 on LPS-induced IL-6. Moreover, AM251, AM630 and SB366791, administered alone, inhibited LPS-induced increases in plasma IL-1, and IL-6 levels. In conclusion, inhibition of endocannabinoid degradation or transport in vivo potentiates LPS-induced increases in circulating TNF-, levels, an effect which may be mediated by PPAR, and is also reduced by pharmacological blockade of CB1, CB2 and TRPV1. The immunosuppressive effect of AM404 on IL-1, levels is mediated by the cannabinoid CB1 receptor. Improved understanding of endocannabinoid-mediated regulation of immune function has fundamental physiological and potential therapeutic significance. [source] Cross-regulation of cannabinoid CB1 and CB2 receptors governs hepatic steatosisLIVER INTERNATIONAL, Issue 10 2010Ying-Ying Yang No abstract is available for this article. [source] Involvement of cannabinoid receptors in inflammatory hypersensitivity to colonic distension in ratsNEUROGASTROENTEROLOGY & MOTILITY, Issue 10 2006M. Sanson Abstract, Activation of cannabinoid CB1 and CB2 receptors is known to attenuate nociception and hyperalgesia in somatic inflammatory conditions. The aim of this study was to determine whether cannabinoids modulate colonic sensitivity in basal and inflammatory conditions. The effects of CB1 and CB2 receptor agonists and antagonists on the abdominal contractile response to colorectal distension (CRD) in basal conditions and after 2,4,6-trinitrobenzenesulphonic acid-induced colitis were investigated. As previously described, colitis triggered a hypersensitivity to CRD. In basal conditions, both CB1 (WIN 55212-2) and CB2 (JWH 015) agonists reduced the abdominal response to CRD at a dose of 1 mg kg,1, i.p. Both compounds were active at a lower dose (0.1 mg kg,1) abolishing the hypersensitivity induced by colitis. Administered alone, CB1 (Rimonabant) and CB2 (SR 144528) receptor antagonists (10 mg kg,1) had no effect on basal sensitivity. In contrast, the CB1, but not the CB2, receptor antagonist enhanced colitis-induced hyperalgesia. It is concluded that colonic inflammation enhances the antinociceptive action of CB1 and CB2 receptor agonists, and activates an endogenous, CB1 receptor mediated, antinociceptive pathway. [source] Anandamide improves the impaired nitric oxide-mediated neurogenic relaxation of the corpus cavernosum in diabetic rats: involvement of cannabinoid CB1 and vanilloid VR1 receptorsBJU INTERNATIONAL, Issue 6 2007Mehdi Ghasemi OBJECTIVE To investigate the ability of acute administration of the endogenous cannabinoid, anandamide, in vitro to alter the nonadrenegic noncholinergic (NANC)-mediated relaxation of corpus cavernosum (CC) in diabetic rats and the possible role of nitric oxide (NO), as it is well known that erectile dysfunction (ED) affects 35,75% of men with diabetes mellitus and several studies have been conducted to find appropriate strategies for treating diabetes-induced ED. MATERIALS AND METHODS Diabetes was induced in rats by streptozotocin administration and was maintained for 8 weeks. The CC were removed and isolated in organ baths for pharmacological studies. Agonist-evoked or electrical-field stimulation (EFS)-evoked smooth muscle tensions in CC strips from control and diabetic rats were measured. RESULTS The neurogenic relaxation of phenylephrine (7.5 µm)-precontracted isolated CC strips was impaired in diabetic rats. Anandamide (0.3, 1 and 3 µm) enhanced the relaxant responses to EFS in diabetic CC strips in a dose-dependent manner. This effect was antagonized by the selective cannabinoid CB1 receptor antagonist AM251 (1 µm) and the selective vanilloid receptor antagonist capsazepine (3 µm). Concurrent administration of partially effective doses of l -arginine (10 µm) and anandamide (0.3 µm) exerted a synergistic improvement in EFS-induced relaxation of diabetic CC strips (P < 0.001). The relaxant responses to the NO donor, sodium nitroprusside, were similar between diabetic and control groups. CONCLUSION For the first time, we show that acute administration of anandamide, an endogenous cannabinoid, alone or combined with l -arginine can improve nitrergic nerve-mediated relaxation of the CC in diabetic rats. This effect was mediated by cannabinoid CB1 and vanilloid VR1 receptors within the CC. [source] Emerging strategies for exploiting cannabinoid receptor agonists as medicinesBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2009Roger G Pertwee Mandarin translation of abstract Medicines that activate cannabinoid CB1 and CB2 receptor are already in the clinic. These are Cesamet® (nabilone), Marinol® (dronabinol; ,9 -tetrahydrocannabinol) and Sativex® (,9 -tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol® can also be prescribed to stimulate appetite, while Sativex® is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB2 receptors; or (v) ,multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. Mandarin translation of abstract [source] Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRIBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2008C-L Chin Background and purpose: Activation of cannabinoid CB1 and/or CB2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB1 from CB2 receptor neural activity using pharmacological MRI (phMRI) in awake rats. Experimental approach: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB1/CB2 (A-834735) and selective CB2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB1 (rimonabant) or CB2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo. Key results: The non-selective CB1/CB2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB1 receptor density binding maps. Pretreatment with a CB1 antagonist but not with a CB2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB2 selective agonist. Conclusion and implications: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB1 and CB2 receptors using phMRI. Further, as the presence of CB2 receptors in the brain remains controversial, our data suggest that if CB2 receptors are expressed, they are not functional under normal physiological conditions. British Journal of Pharmacology (2008) 153, 367,379; doi:10.1038/sj.bjp.0707506; published online 29 October 2007 [source] The ,allosteric modulator' SCH-202676 disrupts G protein-coupled receptor function via sulphydryl-sensitive mechanismsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2006Anna M Lewandowicz Previous studies suggest that the thiadiazole compound SCH-202676 (N -(2,3-diphenyl-1,2,4-thiadiazol-5-(2H)-ylidene)methanamine) acts as an allosteric modulator of a variety of structurally distinct G protein-coupled receptors (GPCRs). It was postulated that SCH-202676 would directly bind a structural motif in the receptor molecule common to divergent members of the GPCR family. The molecular mechanisms of such a promiscuous action, however, remain obscure. To clarify the mechanism of SCH-202676 action, we used the functional approach of [35S]GTP,S autoradiography with rat brain cryostat sections together with classical membrane [35S]GTP,S binding assays to evaluate how the thiadiazole affects G protein activity mediated by various receptors linked to the Gi -family of G proteins. We found that in the absence of dithiotreitol (DTT), SCH-202676 (10,7,10,5 M) elicits nonspecific effects in the [35S]GTP,S-based G protein activation assays, thereby severely compromising interpretations on the compounds ability to allosterically inhibit receptor-mediated G protein activity. Such a nonspecific behaviour was fully reversed upon addition of DTT (1 mM), revealing thiol-based mechanism of action. In routine incubations containing DTT, SCH-202676 had no effect on receptor-driven G protein activity, as assessed for adenosine A1, ,2 -adrenergic, cannabinoid CB1, lysophosphatidic acid LPA1, muscarinic M2/M4, purinergic P2Y12 or sphingosine 1-phosphate receptors, suggesting that the thiadiazole does not act as an allosteric modulator of GPCR function. 1H NMR analysis indicated that SCH-202676 underwent structural changes after incubation with the reducing agent DTT or with brain tissue. We conclude that SCH-202676 modulates GPCRs via thiol modification rather than via true allosteric mechanisms. British Journal of Pharmacology (2006) 147, 422,429. doi:10.1038/sj.bjp.0706624 [source] Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptorsBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2004James D Leggett The ability of the endogenous fatty acid amide, cis -oleamide (ODA), to bind to and activate cannabinoid CB1 and CB2 receptors was investigated. ODA competitively inhibited binding of the nonselective cannabinoid agonist [3H]CP55,940 and the selective CB1 antagonist [3H]SR141716A to rat whole-brain membranes with Ki values of 1.14 ,M (0.52,2.53 ,M, Hill slope=0.80, n=6) and 2.63 ,M (0.62,11.20 ,M, Hill slope=0.92, n=4), respectively. AEA inhibited [3H]CP55,940 binding in rat whole-brain membranes with a Ki of 428 nM (346,510 nM, Hill slope=,1.33, n=3). ODA competitively inhibited [3H]CP55,940 binding in human CB1 (hCB1) cell membranes with a Ki value of 8.13 ,M (4.97,13.32 ,M, n=2). In human CB2 transfected (hCB2) HEK-293T cell membranes, 100 ,M ODA produced only a partial (42.5±7%) inhibition of [3H]CP55,940 binding. ODA stimulated [35S]GTP,S binding in a concentration-dependent manner (EC50=1.64 ,M (0.29,9.32 ,M), R2=0.99, n=4,9), with maximal stimulation of 188±9% of basal at 100 ,M. AEA stimulated [35S]GTP,S binding with an EC50 of 10.43 ,M (4.45,24.42 ,M, R2=1.00, n=3, 195±4% of basal at 300 ,M). Trans -oleamide (trans- ODA) failed to significantly stimulate [35S]GTP,S binding at concentrations up to 100 ,M. ODA (10 ,M)-stimulated [35S]GTP,S binding was reversed by the selective CB1 antagonist SR141716A (IC50=2.11 nM (0.32,13.77 nM), R2=1.00, n=6). The anatomical distribution of ODA-stimulated [35S]GTP,S binding in rat brain sections was indistinguishable from that of HU210. Increases of similar magnitude were observed due to both agonists in the striatum, cortex, hippocampus and cerebellum. ODA (10 ,M) significantly inhibited forskolin-stimulated cyclic AMP (cAMP) accumulation in mouse neuroblastoma N1E 115 cells (P=0.02, n=11). ODA-mediated inhibition was completely reversed by 1 ,M SR141716A (P<0.001, n=11) and was also reversed by pretreatment with 300 ng ml,1 pertussis toxin (P<0.001, n=6). These data demonstrate that ODA is a full cannabinoid CB1 receptor agonist. Therefore, in addition to allosteric modulation of other receptors and possible entourage effects due to fatty acid amide hydrolase inhibition, the effects of ODA may be mediated directly via the CB1 receptor. British Journal of Pharmacology (2004) 141, 253,262. doi:10.1038/sj.bjp.0705607 [source] Involvement of cannabinoids in the cardioprotection induced by lipopolysaccharideBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2001Caroline Lagneux We have examined the involvement of the endocannabinoid system in the cardioprotection triggered by lipopolysaccharide (LPS). Rats were treated with saline or LPS (10 ,g Kg,1). 24 h later, hearts were excised, retrogradely perfused, submitted to a low-flow ischaemia (0.6 ml min,1) for 90 min and reperfused for 60 min. Some hearts were perfused with either SR 141716A (a cannabinoid CB1, receptor antagonist 1 ,M), SR 144528 (a CB2 receptor anagonist ,M), NNLA (3 ,M) or sodium nitroprusside (1 ,M) 5 min before ischaemia and during the ischaemic period. The cardioprotective effects of LPS treatment, in terms of infarction and functional recovery, were not altered by the perfusion of SR 141716A but abolished by both SR 144528 and NNLA. Finally, SR 144528 abolished the beneficial effects of SNP perfusion. Our results suggest an involvement of endocannabinoids, acting through the CB2 receptors, in the cardioprotection triggered by LPS against myocardial ischaemia. This could be attributed to a relationship between cannabinoids and NO. British Journal of Pharmacology (2001) 132, 793,796; doi:10.1038/sj.bjp.0703902 [source] | ||||||||||