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An endocannabinoid mechanism for stress-induced analgesia.

  • Author(s): 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
  • et al.
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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