title: Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.
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.
authors.affiliation: 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.
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.forename: Lamont
authors.initials: L
authors.lastname: Booker
authors.forename: James J
authors.initials: JJ
authors.lastname: Burston
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kinsey
authors.forename: Joel E
authors.initials: JE
authors.lastname: Schlosburg
authors.forename: Franciso J
authors.initials: FJ
authors.lastname: Pavón
authors.forename: Antonia M
authors.initials: AM
authors.lastname: Serrano
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.forename: Loren H
authors.initials: LH
authors.lastname: Parsons
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology; D002186:Cannabinoids; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism*; D006868:Hydrolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D052117:Benzodioxoles; D002186:Cannabinoids; D063388:Endocannabinoids; D005989:Glycerides; D008994:Monoacylglycerol Lipases; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184; C094503:glyceryl 2-arachidonate