An endocannabinoid mechanism for stress-induced analgesia |
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Authors: | Hohmann Andrea G Suplita Richard L Bolton Nathan M Neely Mark H Fegley Darren Mangieri Regina Krey Jocelyn F Walker J Michael Holmes Philip V Crystal Jonathon D Duranti Andrea Tontini Andrea Mor Marco Tarzia Giorgio Piomelli Daniele |
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Institution: | Neuroscience and Behavior Program, Department of Psychology, The University of Georgia, Athens, Georgia 30602-3013, USA. ahohmann@uga.edu |
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Abstract: | Acute stress suppresses pain by activating brain pathways that engage opioid or non-opioid mechanisms. Here we show that an opioid-independent form of this phenomenon, termed stress-induced analgesia, is mediated by the release of endogenous marijuana-like (cannabinoid) compounds in the brain. Blockade of cannabinoid CB(1) receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia. In this region, stress elicits the rapid formation of two endogenous cannabinoids, the lipids 2-arachidonoylglycerol (2-AG) and anandamide. A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase, selectively increases 2-AG concentrations and, when injected into the periaqueductal grey matter, enhances stress-induced analgesia in a CB1-dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase, which selectively elevate anandamide concentrations, exert similar effects. Our results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia. These studies also identify monoacylglycerol lipase as a previously unrecognized therapeutic target. |
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