An endocannabinoid mechanism for stress-induced analgesia.
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.
Neuroscience and Behavior Program, Department of Psychology, The University of Georgia, Athens, Georgia 30602-3013, USA. ahohmann@uga.edu
Andrea G
AG
Hohmann
Richard L
RL
Suplita
Nathan M
NM
Bolton
Mark H
MH
Neely
Darren
D
Fegley
Regina
R
Mangieri
Jocelyn F
JF
Krey
J Michael
JM
Walker
Philip V
PV
Holmes
Jonathon D
JD
Crystal
Andrea
A
Duranti
Andrea
A
Tontini
Marco
M
Mor
Giorgio
G
Tarzia
Daniele
D
Piomelli
D000698:Analgesia; D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000096:biosynthesis / Q000378:metabolism*; D063388:Endocannabinoids; D005989:Glycerides / Q000096:biosynthesis / Q000378:metabolism; D006868:Hydrolysis / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013312:Stress, Physiological / Q000503:physiopathology*
D001095:Arachidonic Acids; D001713:Biphenyl Compounds; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; C501835:URB602; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; C078814:anandamide