Kappa opioid mediation of cannabinoid effects of the potent hallucinogen, salvinorin A, in rodents.

Abstract:

RATIONALE: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. OBJECTIVES: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.

journal_title

Psychopharmacology

authors

Walentiny DM,Vann RE,Warner JA,King LS,Seltzman HH,Navarro HA,Twine CE Jr,Thomas BF,Gilliam AF,Gilmour BP,Carroll FI,Wiley JL

doi

10.1007/s00213-010-1827-6

subject

Has Abstract

pub_date

2010-06-01 00:00:00

pages

275-84

issue

2

eissn

0033-3158

issn

1432-2072

journal_volume

210

pub_type

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