Endocannabinoid Pathway Activated by Nerve Agents

If selectively activated, pathway could result in beneficial analgesic properties

TUESDAY, April 29 (HealthDay News) -- Organophosphorus nerve agents augment the endocannabinoid pathway in the brain, resulting in clinical effects such as that caused by the exogenous cannabinoid, marijuana. Selective activation of this pathway could be used to obtain desirable therapeutic effects such as analgesia, while avoiding unwanted side effects such as hypomotility and cognitive dysfunction, according to research findings published online April 27 in Nature Chemical Biology.

Daniel K. Nomura, of the University of California at Berkeley, and colleagues investigated the effects of an analog of sarin nerve gas, IDFP, and other organophosphorus nerve agents on mice behavior and brain cannabinoid metabolism.

The researchers found that IDFP administration completely blocked the activity of two hydrolytic enzymes, leading to a 10-fold elevation in levels of the principal endogenous cannabinoid ligands 2-AG and anandamide in the brains of mice. This resulted in a constellation of clinical effects consistent with the cannabinoid pathway, including analgesia, hypomotility, hypothermia and catalepsy. These effects were blocked when mice were pre-treated with an inhibitor of the cannabinoid receptor CB1.

These organophosphate agents "elicit full-blown cannabinoid behavioral effects comparable to direct agonists of the CB1 receptor," write the authors. "A critical goal for future endocannabinoid-based therapeutic pursuits will be to attain adequate target selectivity to achieve a beneficial subset of full-blown cannabinoid pharmacology."

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