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Activation of the endocannabinoid system by organophosphorus nerve agents

Abstract

Δ9-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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Figure 1: CB1-dependent effects of IDFP in the tetrad tests for cannabinoid behavior.
Figure 2: Effects of IDFP and CPO on endocannabinoid and AA levels in brain.
Figure 3: Functional proteomic analysis.
Figure 4: Proteomic targets of IDFP and CPO.

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Acknowledgements

This work was supported by grants ES008762 (J.E.C.) and CA087660 (B.F.C.) from the US National Institutes of Health and by the University of California Toxic Substances Research and Teaching Program (D.K.N.). We thank our University of California, Berkeley colleagues H.-S. Sul and M. Ahmadian for equipment in hypothermia experiments, R. Nichiporuk and U. Andersen for advice in the mass spectrometry studies and K. Durkin and T. Clark for graphical assistance. J. Burston, J. Wiley and A. Lichtman of Virginia Commonwealth University provided the data on guanosine triphosphate binding. We thank C. Lupica and A. Zimmer (US National Institutes of Health) for the Cnr1−/− mice.

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D.K.N. designed and performed experiments and wrote the paper. J.L.B., G.M.S., K.F., R.S.I. and A.M.W. performed experiments. B.F.C. and J.E.C. designed experiments and wrote the paper.

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Correspondence to John E Casida.

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Nomura, D., Blankman, J., Simon, G. et al. Activation of the endocannabinoid system by organophosphorus nerve agents. Nat Chem Biol 4, 373–378 (2008). https://doi.org/10.1038/nchembio.86

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