Activation of the endocannabinoid system by organophosphorus nerve agents.
Delta(9)-tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana, has useful medicinal properties but also undesirable side effects. The brain receptor for THC, CB(1), is also activated by the endogenous cannabinoids anandamide and 2-arachidonylglycerol (2-AG). Augmentation of endocannabinoid signaling by blockade of their metabolism may offer a more selective pharmacological approach compared with CB(1) agonists. Consistent with this premise, inhibitors of the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH) produce analgesic and anxiolytic effects without cognitive defects. In contrast, we show that dual blockade of the endocannabinoid-degrading enzymes monoacylglycerol lipase (MAGL) and FAAH by selected organophosphorus agents leads to greater than ten-fold elevations in brain levels of both 2-AG and anandamide and to robust CB(1)-dependent behavioral effects that mirror those observed with CB(1) agonists. Arachidonic acid levels are decreased by the organophosphorus agents in amounts equivalent to elevations in 2-AG, which indicates that endocannabinoid and eicosanoid signaling pathways may be coordinately regulated in the brain.
Nomura
Daniel K
DK
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, 114 Wellman Hall, Berkeley, California 94720-3112, USA.
Blankman
Jacqueline L
JL
Simon
Gabriel M
GM
Fujioka
Kazutoshi
K
Issa
Roger S
RS
Ward
Anna M
AM
Cravatt
Benjamin F
BF
Casida
John E
JE
D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D016718:Arachidonic Acid / Q000032:analysis; D001095:Arachidonic Acids / Q000032:analysis; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D063388:Endocannabinoids; D005260:Female; D005989:Glycerides / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008968:Molecular Conformation; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000032:analysis; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000187:drug effects; D043882:Receptors, Cannabinoid / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D008994:Monoacylglycerol Lipases; D009943:Organophosphorus Compounds; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; D000099252:Fatty Acid Amide Hydrolases; C094503:glyceryl 2-arachidonate; C078814:anandamide