Genetic inactivation and prolonged pharmacologic inhibition of monoacylglycerol lipase have opposite effects on anesthetic sensitivity to propofol.

Monoacylglycerol lipase (MGL) is a major enzyme involved in degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Selective inhibitors of MGL are regarded as promising analgesics and anticancer agents. To gain insight into the possible consequences of their prolonged administration for anesthetic action, the effects of several inhalational and intravenous anesthetics were tested in knockout mice lacking the MGL gene in the loss of righting reflex (LORR) assay. Sensitivity to inhalational and most intravenous anesthetics was not altered in knockout mice. However, compared with wild-type littermates, they showed increased sensitivity to the intravenous anesthetic propofol. Permanently elevated levels of 2-AG after MGL knockout are known to cause desensitization of cannabinoid (CB1) receptors, which have been advocated as possible mediators of propofol anesthesia. Therefore, increased sensitivity to propofol in knockout mice at first suggested that 2-AG may potentiate CB1 receptors despite their hypofunction in these animals. Pharmacologic inhibition of MGL also causes desensitization of CB1 receptors, so sensitivity to propofol was tested further in C57BL/6N mice pretreated chronically with the selective MGL inhibitor JZL 184. Contrary to the results in knockout mice, these animals showed drastically reduced sensitivity to propofol. The reason for increased sensitivity to propofol after MGL knockout remains unclear, but may result from changes occurring in these animals during development. However, our results in C57BL/6N mice pretreated with JZL 184 confirmed the role of CB1 receptors in propofol anesthesia advocated previously, and also suggest that prolonged use of MGL inhibitors may be associated with the development of resistance to propofol.