Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system.
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.
Schlosburg
Joel E
JE
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
Blankman
Jacqueline L
JL
Long
Jonathan Z
JZ
Nomura
Daniel K
DK
Pan
Bin
B
Kinsey
Steven G
SG
Nguyen
Peter T
PT
Ramesh
Divya
D
Booker
Lamont
L
Burston
James J
JJ
Thomas
Elizabeth A
EA
Selley
Dana E
DE
Sim-Selley
Laura J
LJ
Liu
Qing-song
QS
Lichtman
Aron H
AH
Cravatt
Benjamin F
BF
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
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