| 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 |
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: | https://orca.cardiff.ac.uk/id/eprint/112073 |
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