Article abstract
Nature Chemical Biology 5, 37 - 44 (2008)
Published online: 23 November 2008 | doi:10.1038/nchembio.129
Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects
Jonathan Z Long1, Weiwei Li1, Lamont Booker3, James J Burston3, Steven G Kinsey3, Joel E Schlosburg3, Franciso J Pavón2, Antonia M Serrano2, Dana E Selley3, Loren H Parsons2, Aron H Lichtman3 & Benjamin F Cravatt1
Abstract
2-Arachidonoylglycerol (2-AG) and anandamide are endocannabinoids that activate the cannabinoid receptors CB1 and CB2. Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that for anandamide is mediated by fatty acid amide hydrolase (FAAH), and for 2-AG is thought to involve monoacylglycerol lipase (MAGL). FAAH inhibitors produce a select subset of the behavioral effects observed with CB1 agonists, which suggests a functional segregation of endocannabinoid signaling pathways in vivo. Testing this hypothesis, however, requires specific tools to independently block anandamide and 2-AG metabolism. Here, we report a potent and selective inhibitor of MAGL called JZL184 that, upon administration to mice, raises brain 2-AG by eight-fold without altering anandamide. JZL184-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia and hypomotility. These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.
- The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
- The Committee on the Neurobiology of Addiction, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, USA.
Correspondence to: Benjamin F Cravatt1 e-mail: cravatt@scripps.edu
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