Kappa opioid mediation of cannabinoid effects of the potent hallucinogen, salvinorin A, in rodents.
Psychopharmacology – June 01, 2010
Source: PubMed
Summary
Could a potent hallucinogen, salvinorin A, activate the same brain systems as cannabis? Researchers explored this by testing salvinorin A’s interaction with cannabinoid receptors and its impact on rodents. The investigation revealed that salvinorin A's pronounced effects, such as reduced movement and pain relief, are driven by its direct activation of kappa-opioid receptors. Importantly, it showed no direct engagement with the endocannabinoid system. This clarifies that salvinorin A's unique pharmacological profile stems purely from its kappa-opioid pathway, not cannabis-like mechanisms, providing a clearer understanding of its actions.
Abstract
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. This study represents a systematic examination of this hypothesis. 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. 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. 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.