Kappa opioid mediation of cannabinoid effects of the potent hallucinogen, salvinorin A, in rodents.
BACKGROUND
Salvinorin A, the primary psychoactive derivative of the hallucinogenic herb Salvia divinorum, is a potent and highly selective kappa-opioid receptor (KOR) agonist. Several recent studies, however, have suggested endocannabinoid system mediation of some of its effects.


OBJECTIVE
This study represents a systematic examination of this hypothesis.


METHODS
Salvinorin A was isolated from S. divinorum and was evaluated in a battery of in vitro and in vivo procedures designed to detect cannabinoid activity, including CB(1) receptor radioligand and [(35)S]GTPgammaS binding, calcium flux assay, in vivo cannabinoid screening tests, and drug discrimination.


RESULTS
Salvinorin A did not bind to nor activate CB(1) receptors. In vivo salvinorin A produced pronounced hypolocomotion and antinociception (and to a lesser extent, hypothermia). These effects were blocked by the selective KOR antagonist, JDTic, but not by the CB(1) receptor antagonist rimonabant. Interestingly, however, rimonabant attenuated KOR activation stimulated by U69,593 in a [(35)S]GTPgammaS assay. Salvinorin A did not substitute for Delta(9)-tetrahydrocannabinol (THC) in mice trained to discriminate THC.


CONCLUSIONS
These findings suggest that similarities in the pharmacological effects of salvinorin A and those of cannabinoids are mediated by its activation of KOR rather than by any direct action of salvinorin A on the endocannabinoid system. Further, the results suggest that rimonabant reversal of salvinorin A effects in previous studies may be explained in part by rimonabant attenuation of KOR activation.
Walentiny
D Matthew
DM
Department of Pharmacology and Toxicology, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298-0613, USA.
Vann
Robert E
RE
Warner
Jonathan A
JA
King
Lindsey S
LS
Seltzman
Herbert H
HH
Navarro
Hernán A
HA
Twine
Charles E
CE
Thomas
Brian F
BF
Gilliam
Anne F
AF
Gilmour
Brian P
BP
Carroll
F Ivy
FI
Wiley
Jenny L
JL
D000818:Animals; D002118:Calcium / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000502:physiology; D004193:Discrimination Learning; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D013759:Dronabinol / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D010147:Pain Measurement; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011869:Radioligand Assay; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D027544:Salvia; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
C433814:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide; D063385:Cannabinoid Receptor Modulators; D045785:Diterpenes, Clerodane; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D017473:Receptors, Opioid, kappa; D044005:Tetrahydroisoquinolines; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013759:Dronabinol; D000077285:Rimonabant; D002118:Calcium; C090499:salvinorin A