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Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects

Long, Jonathan Z, Li, Weiwei, Booker, Lamont, Burston, James J, Kinsey, Steven G, Schlosburg, Joel E, Pavón, Franciso J, Serrano, Antonia M, Selley, Dana E, Parsons, Loren H, Lichtman, Aron H and Cravatt, Benjamin F 2008. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nature Chemical Biology 5 (1) , pp. 37-44. 10.1038/nchembio.129

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Nature Publishing Group
ISSN: 1552-4450
Date of Acceptance: 23 November 2008
Last Modified: 10 Jul 2018 14:30
URI: http://orca.cardiff.ac.uk/id/eprint/112073

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