Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia.
Recent work in our laboratories has demonstrated that an opioid-independent form of stress-induced analgesia (SIA) is mediated by endogenous cannabinoids [Hohmann et al., 2005. Nature 435, 1108]. Non-opioid SIA, induced by a 3-min continuous foot shock, is characterized by the mobilization of two endocannabinoid lipids--2-arachidonoylglycerol (2-AG) and anandamide--in the midbrain periaqueductal gray (PAG). The present studies were conducted to examine the contributions of spinal endocannabinoids to nonopioid SIA. Time-dependent increases in levels of 2-AG, but not anandamide, were observed in lumbar spinal cord extracts derived from shocked relative to non-shocked rats. Notably, 2-AG accumulation was of smaller magnitude than that observed previously in the dorsal midbrain following foot shock. 2-AG is preferentially degraded by monoacylglycerol lipase (MGL), whereas anandamide is hydrolyzed primarily by fatty-acid amide hydrolase (FAAH). This metabolic segregation enabled us to manipulate endocannabinoid tone at the spinal level to further evaluate the roles of 2-AG and anandamide in nonopioid SIA. Intrathecal administration of the competitive CB1 antagonist SR141716A (rimonabant) failed to suppress nonopioid SIA, suggesting that supraspinal rather than spinal CB1 receptor activation plays a pivotal role in endocannabinoid-mediated SIA. By contrast, spinal inhibition of MGL using URB602, which selectively inhibits 2-AG hydrolysis in the PAG, enhanced SIA through a CB1-selective mechanism. Spinal inhibition of FAAH, with either URB597 or arachidonoyl serotonin (AA-5-HT), also enhanced SIA through a CB1-mediated mechanism, presumably by increasing accumulation of tonically released anandamide. Our results suggest that endocannabinoids in the spinal cord regulate, but do not mediate, nonopioid SIA.
Suplita
Richard L
RL
Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Baldwin Street, Athens, GA 30602-3013, USA.
Gutierrez
Tannia
T
Fegley
Darren
D
Piomelli
Daniele
D
Hohmann
Andrea G
AG
D000698:Analgesia; D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D001522:Behavior, Animal; D001549:Benzamides / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D010147:Pain Measurement / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D000077285:Rimonabant; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology; D013997:Time Factors
D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; C114007:arachidonoylserotonin; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D012701:Serotonin; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant; C078814:anandamide