Cannabinoid modulation of dynorphin A: correlation to cannabinoid-induced antinociception.
Intrathecal administration of anandamide, delta9-tetrahydrocannabinol (THC) and (-)-3-[2-hydroxy-4-(1,1-dimethyheptyl)ptyl)phenyl]-4-(3-hydr oxypropyl)-cicloexan-1-ol (CP55,940) induced spinal antinociception accompanied by differential kappa-opioid receptor involvement and dynorphin A peptide release. Antinociception using the tail-flick test was induced by the classical cannabinoid THC and was blocked totally by 17,17'-bis(cyclopropylmethyl)-6',6,7,7'-tetrahydro-4,5,4'5'-diepoxy++ +-6,6'-(imino)[7,7'-bimorphinan]-3,3',14,14'-tetrol (norbinaltorphimine) indicating a significant and critical kappa-opioid receptor component. The endogenous cannabinoid, anandamide and the non-classical bicyclic cannabinoid, CP55,940, induced non-nor-BNI-sensitive effects. The N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazo le-carboxamide (SR141716A)-mediated attenuation of spinal antinociception imparted by the various cannabinoids indicates cannabinoid CB1 receptor involvement. THC-induced an enhancement of immunoreactive dynorphin A release which coincided with the onset, but not duration antinociception. The release of dynorphin A was also attenuated by SR141716A suggesting it is cannabinoid CB1 receptor-mediated. These data indicate a critical role for dynorphin A release in the initiation of the antinociceptive effects of the cannabinoids at the spinal level.
Mason
D J
DJ
Department of Pharmacology and Toxicology, Virginia Commonwealth University/Medical College of Virginia, Richmond 23298-0613, USA.
Lowe
J
J
Welch
S P
SP
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003511:Cyclohexanols / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D013759:Dronabinol / Q000494:pharmacology; D004399:Dynorphins / Q000134:cerebrospinal fluid / Q000187:drug effects*; D007278:Injections, Spinal; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077285:Rimonabant
D000700:Analgesics; D002186:Cannabinoids; D003511:Cyclohexanols; D009292:Narcotic Antagonists; D010880:Piperidines; D011720:Pyrazoles; C051844:norbinaltorphimine; D009271:Naltrexone; D004399:Dynorphins; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant; D004121:Dimethyl Sulfoxide