Jacob Bell
New Member
Nature Chemical Biology 4, 373 - 378 (2008)
Published online: 27 April 2008 | doi:10.1038/nchembio.86
Activation of the endocannabinoid system by organophosphorus nerve agents
Daniel K Nomura1, Jacqueline L Blankman2, Gabriel M Simon2, Kazutoshi Fujioka1, Roger S Issa1, Anna M Ward1, Benjamin F Cravatt2 & John E Casida1
Abstract
Delta9-Tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana, has useful medicinal properties but also undesirable side effects. The brain receptor for THC, CB1, 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 CB1 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 CB1-dependent behavioral effects that mirror those observed with CB1 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.
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Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, 114 Wellman Hall, Berkeley, California 94720-3112, USA.
The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037-1000, USA.
Source: Activation of the endocannabinoid system by organophosphorus nerve agents
Published online: 27 April 2008 | doi:10.1038/nchembio.86
Activation of the endocannabinoid system by organophosphorus nerve agents
Daniel K Nomura1, Jacqueline L Blankman2, Gabriel M Simon2, Kazutoshi Fujioka1, Roger S Issa1, Anna M Ward1, Benjamin F Cravatt2 & John E Casida1
Abstract
Delta9-Tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana, has useful medicinal properties but also undesirable side effects. The brain receptor for THC, CB1, 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 CB1 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 CB1-dependent behavioral effects that mirror those observed with CB1 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.
Top of page
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, 114 Wellman Hall, Berkeley, California 94720-3112, USA.
The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037-1000, USA.
Source: Activation of the endocannabinoid system by organophosphorus nerve agents
