Involvement of kappa-opioid and endocannabinoid system on Salvinorin A-induced reward.
BACKGROUND
The recreational drug, Salvinorin A, derived from the plant of Salvia divinorum, is a potent and selective kappa-opioid receptor agonist. The abuse of selective k-agonists is a novel phenomenon, the mechanism of which is not fully understood.


METHODS
We investigated salvinorin A given SC on the conditioned place preference (.05-160 microg/kg) and intracerebroventricular (ICV) self-administration (.01-1 microg/infusion) paradigms, in Wistar rats.


RESULTS
The present results demonstrate the rewarding effects of Salvinorin A in a range of doses between .1 and 40 microg/kg SC for conditioned place preference test and .1-.5 microg/infusion for ICV self-administration. Highest doses (160 microg/kg for conditioned place preference test and 1 microg/infusion for ICV self-administration) were aversive. The rewarding effect was antagonized by intraperitoneal (IP) pretreatment with the cannabinoid CB(1) receptor antagonist, rimonabant [N-piperidino-5-(4-chlorophenyl)1-(2,4-dichloro phenyl)-4 methyl pyrazole 3-carboxamide] (1 mg/kg), and the kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI) (10 mg/kg). In the shell of nucleus accumbens, dopamine extracellular levels were increased after administration of salvinorin A (40 microg/kg SC), reaching a maximum value of about 150%.


CONCLUSIONS
These data provide the demonstration of the rewarding effects of Salvinorin A through an interaction between kappa-opioid and (endo)cannabinoid system in rats.
Braida
Daniela
D
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy.
Limonta
Valeria
V
Capurro
Valeria
V
Fadda
Paola
P
Rubino
Tiziana
T
Mascia
Paola
P
Zani
Alessia
A
Gori
Enzo
E
Fratta
Walter
W
Parolaro
Daniela
D
Sala
Mariaelvina
M
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors / Q000502:physiology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D045785:Diterpenes, Clerodane; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D063388:Endocannabinoids; D008297:Male; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000502:physiology*; D012201:Reward; D000077285:Rimonabant; D012646:Self Administration
D000975:Antioxidants; D063385:Cannabinoid Receptor Modulators; D004224:Diterpenes; D045785:Diterpenes, Clerodane; D063388:Endocannabinoids; D009292:Narcotic Antagonists; D010880:Piperidines; D011720:Pyrazoles; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D000077285:Rimonabant; C090499:salvinorin A; D004298:Dopamine