RT Journal Article SR Electronic T1 Monoacylglycerol Lipase Activity Is a Critical Modulator of the Tone and Integrity of the Endocannabinoid System JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 996 OP 1003 DO 10.1124/mol.110.068304 VO 78 IS 6 A1 Pranab K. Chanda A1 Ying Gao A1 Lilly Mark A1 Joan Btesh A1 Brian W. Strassle A1 Peimin Lu A1 Michael J. Piesla A1 Mei-Yi Zhang A1 Brendan Bingham A1 Albert Uveges A1 Dianne Kowal A1 David Garbe A1 Evguenia V. Kouranova A1 Robert H. Ring A1 Brian Bates A1 Menelas N. Pangalos A1 Jeffrey D. Kennedy A1 Garth T. Whiteside A1 Tarek A. Samad YR 2010 UL http://molpharm.aspetjournals.org/content/78/6/996.abstract AB Endocannabinoids are lipid molecules that serve as natural ligands for the cannabinoid receptors CB1 and CB2. They modulate a diverse set of physiological processes such as pain, cognition, appetite, and emotional states, and their levels and functions are tightly regulated by enzymatic biosynthesis and degradation. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid in the brain and is believed to be hydrolyzed primarily by the serine hydrolase monoacylglycerol lipase (MAGL). Although 2-AG binds and activates cannabinoid receptors in vitro, when administered in vivo, it induces only transient cannabimimetic effects as a result of its rapid catabolism. Here we show using a mouse model with a targeted disruption of the MAGL gene that MAGL is the major modulator of 2-AG hydrolysis in vivo. Mice lacking MAGL exhibit dramatically reduced 2-AG hydrolase activity and highly elevated 2-AG levels in the nervous system. A lack of MAGL activity and subsequent long-term elevation of 2-AG levels lead to desensitization of brain CB1 receptors with a significant reduction of cannabimimetic effects of CB1 agonists. Also consistent with CB1 desensitization, MAGL-deficient mice do not show alterations in neuropathic and inflammatory pain sensitivity. These findings provide the first genetic in vivo evidence that MAGL is the major regulator of 2-AG levels and signaling and reveal a pivotal role for 2-AG in modulating CB1 receptor sensitization and endocannabinoid tone.