Beenhead
Bluelight Crew
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
D9-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.
It came in this months Nature: Chemical Biology. I cannot figure out how to add a adobe attachment though...
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
D9-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.
It came in this months Nature: Chemical Biology. I cannot figure out how to add a adobe attachment though...
