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 analgesia¹, is mediated by the release of endogenous marijuana-like (cannabinoid) compounds in the brain. Blockade of cannabinoid CB₁ 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-arachidonoylglycerol² (2-AG) and anandamide³. A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase^{4, 5}, 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 hydrolase⁶, 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.

1. Neuroscience and Behavior Program, Department of Psychology, The University of Georgia, Athens, Georgia 30602-3013, USA
2. Department of Pharmacology and Center for Drug Discovery, University of California, Irvine, California 92697-4260, USA
3. Schrier Research Laboratory, Departments of Psychology and Neuroscience, Brown University, Providence, Rhode Island 02912, USA
4. Institute of Medicinal Chemistry, University of Urbino Carlo Bo, I-61029 Urbino, Italy
5. Pharmaceutical Department, University of Parma, I-43100 Parma, Italy

Correspondence to: Andrea G. Hohmann¹Daniele Piomelli² Correspondence and requests for materials should be addressed to A.G.H. (Email: ahohmann@uga.edu) or D.P. (Email: piomelli@uci.edu).

Received 23 February 2005; Accepted 18 April 2005

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