title: Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system.
abstract: Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. We found that a similar form of functional antagonism was produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol. After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to cannabinoid receptor (CB1) agonists in mice, effects that were phenocopied by genetic disruption of Mgll (encoding MAGL). Chronic MAGL blockade also caused physical dependence, impaired endocannabinoid-dependent synaptic plasticity and desensitized brain CB1 receptors. These data contrast with blockade of fatty acid amide hydrolase, an enzyme that degrades the other major endocannabinoid anandamide, which produced sustained analgesia without impairing CB1 receptors. Thus, individual endocannabinoids generate distinct analgesic profiles that are either sustained or transitory and associated with agonism and functional antagonism of the brain cannabinoid system, respectively.
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
authors: Joel E
authors: JE
authors: Schlosburg
authors: Jacqueline L
authors: JL
authors: Blankman
authors: Jonathan Z
authors: JZ
authors: Long
authors: Daniel K
authors: DK
authors: Nomura
authors: Bin
authors: B
authors: Pan
authors: Steven G
authors: SG
authors: Kinsey
authors: Peter T
authors: PT
authors: Nguyen
authors: Divya
authors: D
authors: Ramesh
authors: Lamont
authors: L
authors: Booker
authors: James J
authors: JJ
authors: Burston
authors: Elizabeth A
authors: EA
authors: Thomas
authors: Dana E
authors: DE
authors: Selley
authors: Laura J
authors: LJ
authors: Sim-Selley
authors: Qing-song
authors: QS
authors: Liu
authors: Aron H
authors: AH
authors: Lichtman
authors: Benjamin F
authors: BF
authors: Cravatt
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D052117:Benzodioxoles / Q000008:administration & dosage / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D052117:Benzodioxoles; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184