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.