Endocannabinoids Mediate Stress-Induced Analgesia

Abstract

Acute stress decreases pain perception. Hohmann et al. show that, in rats, endocannabinoid signaling is involved in mediating stress-induced analgesia (SIA): Antagonists of the CB 1 endocannabinoid receptor block SIA, as does chronic exposure to CB1 agonists (which produces tolerance to cannabinoids), but opiate antagonists do not. Rats sacrificed at various times after exposure to foot shock (an acute stress) showed increased concentration of 2-arachidonoylglycerol (2-AG) in the dorsal midbrain after 2 minutes and a return to baseline for this endocannabinoid by 15 minutes. The concentration of anandamide peaked approximately 15 minutes after shock. The authors developed a selective inhibitor (an N -biphenyl carbamate) of the 2-AG-hydrolyzing enzyme monoacylglycerol lipase (MGL) and showed that microinjection of this inhibitor into the periaqueductal gray region enhanced SIA and that this effect was blocked by administration of the CB 1 antagonist rimonabant. Inhibition of the anandamide-metabolizing enzyme also enhanced SIA, and this was also blocked by rimonabant. Thus, endocannabinoid-metabolizing enzymes may serve as targets for treatment of pain and stress disorders. A. G. Hohmann, R. L. Suplita, N. M. Bolton, M. H. Neely, D. Fegley, R. Mangieri, J. F. Krey, J. M. Walker, P. V. Holmes, J. D. Crystal, A. Duranti, A. Tontini, M. Mor, G. Tarzia, D. Piomelli, An endocannabinoid mechanism for stress-induced analgesia. Nature 435 , 1108-1112 (2005). [PubMed]