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Endocannabinoids such as anandamide [N-arachidonoylethanolamine (AEA)] and 2-arachidonoyl glycerol (2-AG) are known orexigenic mediators that act via CB1 receptors in hypothalamus and limbic forebrain to induce appetite and stimulate food intake. Circulating endocannabinoid levels inversely correlate with plasma levels of leptin, an anorexigenic mediator that reduces food intake by acting on hypothalamic receptors. Recently, taste has been found to be a peripheral target of leptin. Leptin selectively suppresses sweet taste responses in wild-type mice but not in leptin receptor-deficient db/db mice. Here, we show that endocannabinoids oppose the action of leptin to act as enhancers of sweet taste. We found that administration of AEA or 2AG increases gustatory nerve responses to sweeteners in a concentration-dependent manner without affecting responses to salty, sour, bitter, and umami compounds. The cannabinoids increase behavioral responses to sweet-bitter mixtures and electrophysiological responses of taste receptor cells to sweet compounds. Mice genetically lacking CB1 receptors show no enhancement by endocannnabinoids of sweet taste responses at cellular, nerve, or behavioral levels. In addition, the effects of endocannabinoids on sweet taste responses of taste cells are diminished by AM251, a [CB.sub.1] receptor antagonist, but not by AM630, a [CB.sub.2] receptor antagonist. Immunohistochemistry shows that [CB.sub.1] recaptors are expressed in type II taste cells that also express the T1r3 sweet taste receptor component. Taken together, these observations suggest that the taste organ is a peripheral target of endocannabinoids.' Reciprocal regulation of peripheral sweet taste reception by endocannabinoids and leptin may contribute to their opposing actions on food intake and play an important role in regulating energy homeostasis. energy homeostasis | gustation | reciprocal regulation www.pnas.org/cgi/doi/10.1073/pnas.0912048107

The endogenous cannabinoid system plays an important role in the regulation of gastrointestinal function in health and disease. Endocannabinoid levels are regulated by catabolic enzymes. Here, we describe the presence and localization of monoacylglycerol lipase (MGL), the major enzyme responsible for the degradation of 2-arachidonoylglycerol. We used molecular, biochemical, immunohistochemical, and functional assays to characterize the distribution and activity of MGL. MGL mRNA was present in rat ileum throughout the wall of the gut. MGL protein was distributed in the muscle and mucosal layers of the ileum and in the duodenum, proximal colon, and distal colon. We observed MGL expression in nerve cell bodies and nerve fibers of the enteric nervous system. There was extensive colocalization of MGL with PGP 9.5 and calretinin-immunoreactive neurons, but not with nitric oxide synthase. MGL was also present in the epithelium and was highly expressed in the small intestine. Enzyme activity levels were highest in the duodenum and decreased along the gut with lowest levels in the distal colon. We observed both soluble and membrane-associated enzyme activities. The MGL inhibitor URB602 significantly inhibited whole gut transit in mice, an action that was abolished in cannabinoid 1 receptor-deficient mice. In conclusion, MGL is localized in the enteric nervous system where endocannabinoids regulate intestinal motility. MGL is highly expressed in the epithelium, where this enzyme may have digestive or other functions yet to be determined. endocannabinoids; enteric nervous system; URB602; 2-arachidonoyl glycerol

Cannabis sativa is one of the oldest herbal plants in the history of medicine. It was used in various therapeutic applications from pain to epilepsy, but its psychotropic effect has reduced its usage in recent medical practice. However, renewed interest has been fueled by major discoveries revealing that cannabis-derived compounds act through a signaling pathway in the human body. Here we review recent advances showing that endocannabinoid signaling is a key regulator of synaptic communication throughout the central nervous system. Its underlying molecular architecture is highly conserved in synapses from the spinal cord to the neocortex, and as a negative feed-back signal, it provides protection against excess presynaptic activity. The endocannabinoid signaling machinery operates on demand in a synapse-specific manner; therefore, its modulation offers new therapeutic opportunities for the selective control of deleterious neuronal activity in several neurological disorders., Molecular architecture of synaptic endocannabinoid signaling The core concept of neuronal communication involves the synaptic junction as the major site where chemical neurotransmitters convey information from presynaptic neurons to their [...]

Targeting cannabinoid-2 ([CB.sub.2]) receptors with selective agonists may represent a novel therapeutic avenue in various inflammatory diseases, but the mechanisms by which [CB.sub.2] activation exerts its anti-inflammatory effects and the cellular targets are elusive. Here, we investigated the effects of [CB.sub.2]-receptor activation on TNF-[alpha]-induced signal transduction in human coronary artery endothelial cells in vitro and on endotoxin-induced vascular inflammatory response in vivo. TNF-[alpha] induced NF-[kappa]B and RhoA activation and upregulation of adhesion molecules ICAM-1 and VCAM-1, increased expression of monocyte chemoattractant protein, enhanced transendothelial migration of monocytes, and augmented monocyte-endothelial adhesion. Remarkably, all of the above-mentioned effects of TNF-[alpha] were attenuated by [CB.sub.2] agonists. [CB.sub.2] agonists also decreased the TNF-[alpha]- and/or endotoxin-induced ICAM-1 and VCAM-1 expression in isolated aortas and the adhesion of monocytes to aortic vascular endothelium. [CB.sub.1] and [CB.sub.2] receptors were detectable in human coronary artery endothelial cells by Western blotting, RT-PCR, real-time PCR, and immunofluorescence staining. Because the above-mentioned TNF-[alpha]-induced phenotypic changes are critical in the initiation and progression of atherosclerosis and restenosis, our findings suggest that targeting [CB.sub.2] receptors on endothelial cells may offer a novel approach in the treatment of these pathologies. endothelial activation; inflammation; RhoA; adhesion molecules

Two types of cannabinoid receptor have been cloned and characterized. Whereas C[B.sub.1] receptors are ubiquitously expressed in neurons of the CNS, C[B.sub.2] receptors have been thought to be absent from the CNS. Recent data now question this notion and support the expression of C[B.sub.2] receptors in microglial cells, astrocytes and even some neuron subpopulations. This discrete distribution makes C[B.sub.2] receptors interesting targets for treating neurological disorders because C[B.sub.2]-selective agonists lack psychoactivity. Here, we review evidence supporting the idea that C[B.sub.2] receptors are implicated in the control of fundamental neural cell processes, such as proliferation and survival, and that their pharmacological manipulation might be useful for both delaying the progression of neurodegenerative disorders and inhibiting the growth of glial tumors.

A variety of physical and psychological stressors induce analgesia by activating descending systems that project from the brain to the spinal cord. This stress-induced analgesia (SIA) is mediated by distinct opioid--and nonopioid-dependent mechanisms. New evidence suggests that non-opioid SIA is mediated by two independent endocannabinoids within the midbrain. Furthermore, novel agents that disrupt breakdown of these endocannabinoids enhance non-opioid SIA and pave the way for novel therapies.

In overweight and obese patients, rimonabant, a selective cannabinoid-1 receptor blocker, promotes modest but sustained losses in weight, waist circumference, and lipid levels, say researchers at St. Luke's-Roosevelt Hospital in [...]