Selective Modulation of Endocannabinoid System

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The use of cannabis for ritual or medicinal purposes can be traced to prehistory, although today its use is controversial. Cannabinoids, the active constituents of cannabis, were first discovered in the 1940s but it wasn’t until the 1980s that the receptors for these plant substances were identified. There are two known cannabinoid receptors, CB1 and CB2. CB1 receptors are found primarily in the brain and appear to be responsible for the euphoric and anticonvulsive effects of cannabis whereas CB2 receptors are found almost exclusively in cells of the immune system. More recently, the endogenous lipids, 2-arachidonoylglycerol and anandamide, have been found to bind to cannabinoid receptors. Studies have revealed a broad role for endocannabinoid signalling in a variety of physiological processes including appetite, pain sensation, inflammatory response, mood and memory. An article in Nature Chemical Biology now further elucidates these pathways.

JZL184Signalling by endocannabinoids is terminated by enzymatic hydrolysis which, for anandamide, is mediated by fatty acid amide hydrolase and, for 2-arachidonoylglycerol, is thought to involve monoacylglycerol lipase; selective inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase would allow a better understanding of the roles of the two endocannabinoids. Inhibitors of fatty acid amide hydrolase have been available for some time, and have been shown to reduce pain, inflammation and anxiety by increasing levels of anandamide. For the first time, a selective inhibitor of monoacylglycerol lipase, JZL184, has now been identified. When administered to mice, JZL184 increased levels of 2-arachidonoylglycerol in the brain by about 8-fold, with no effect on levels of anandamide. Treatment with JZL184 produced analgesic effects similar to those achieved with fatty acid amide hydrolase inhibitors, but also produced other effects associated with CB1 agonism, namely hypothermia and hypomotility. If these effects can be controlled, inhibition of monoacylglycerol lipase may provide an alternative means of modulating the endocannabinoid system to alleviate pain.

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