Drug Discovery Opinion

The cannabinoid receptors, CB₁ and CB₂, were first identified as the receptors for the active components of Cannabis sativa. The endogenous ligands for the cannabinoid receptors, anandamide (from ananda, a Sanskrit word meaning ‘bliss’) and 2-arachidonoylglycerol (2-AG), exert most of their analgesic affects through binding to the main cannabinoid receptor in the brain, CB₁. Attempts to prepare CB₁ agonists that mimic the analgesic effects of the main component of cannabis, Δ9-tetrahydrocannabinol (THC) but have reduced potential for memory impairment, locomotor dysfunction, and possibly addiction have met with limited success and a recent alternative approach has been to devise ways of preventing the breakdown of anandamide and 2-AG. Signalling by the endocannabinoids is terminated by enzymatic hydrolysis which, for anandamide, is mediated by fatty acid amide hydrolase (FAAH) and, for 2-arachidonoylglycerol, by monoacylglycerol lipase (MAGL).

Inhibitors of both FAAH and MAGL produce analgesic effects but scientists at the Scripps Research Institute, Virginia Commonwealth University and the Medical College of Wisconsin have now shown that the effects of blocking MAGL are short-lived compared with the effects of blocking FAAH. Although a single injection of the MAGL inhibitor, JZL184, reduced pain in the mouse, after six consecutive daily injections, the effect disappeared. The chronically treated animals also became less sensitive to THC or the synthetic CB₁ agonist, WIN55,212-2, and showed characteristic drug withdrawal symptoms when treated with the CB₁ blocker, rimonabant.

Further tests showed that CB₁ receptors were down-regulated in some brain areas of mice treated for 6 days with JZL184. Genetic disruption of MAGL also resulted in elevated levels of 2-AG and desensitised the CB₁ signalling system, suggesting that chronic inhibition of MAGL may not provide effective analgesia. In contrast, chronic treatment with a FAAH inhibitor to boost anandamide levels did not lead to desensitisation of the CB₁ system.

Although the team do not yet understand why chronic administration of FAAH inhibitors and MAGL inhibitors should produce such strikingly different results, the study, which is published in Nature Neuroscience, suggests that complete blockade of MAGL may not provide effective analgesia over the longer term.

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