期刊
NATURE CHEMICAL BIOLOGY
卷 5, 期 1, 页码 37-44出版社
NATURE RESEARCH
DOI: 10.1038/nchembio.129
关键词
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资金
- US National Institutes of Health [DA017259, DA025285, DA007027, DA005274, AA014619, DA024194, AA06420]
- Helen L. Dorris Institute Child and Adolescent Neuro-Psychiatric Disorder Institute
- Skaggs Institute for Chemical Biology
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [P50AA006420, P60AA006420, R01AA014619] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA025285, T32DA007027, R01DA015683, R01DA003672, P01DA017259, P20DA024194, P50DA005274] Funding Source: NIH RePORTER
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.
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