The discriminative effects of the κ-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects

Abstract

RATIONALE: The widely available hallucinogen salvinorin A is a unique example of a plant-derived compound selective for κ-opioid receptors and may produce effects distinct from those of other compounds with classic hallucinogenic or dissociative properties which are also abused in humans. OBJECTIVES: The objective of this study is to characterize the salvinorin A discriminative cue in nonhuman primates with high κ-receptor genetic homology to humans. METHODS: Adult rhesus monkeys (n=3) were trained to discriminate salvinorin A (0.015 mg/kg, s.c.) from vehicle, in a food-reinforced operant discrimination assay. Parallel studies, using unconditioned behavioral endpoints (facial relaxation and ptosis) also evaluated the κ-opioid receptor mediation of salvinorin A in vivo function. RESULTS: Monkeys trained to discriminate salvinorin A generalized structurally diverse, centrally penetrating κ-agonists (bremazocine, U69,593, and U50,488). By contrast, μ- and δ-opioid agonists (fentanyl and SNC80, respectively) were not generalized, nor were the serotonergic 5HT2 hallucinogen psilocybin or the dissociative N-methyl-D-aspartic acid antagonist, ketamine. The discriminative effects of salvinorin A were blocked by the opioid antagonist quadazocine (0.32 mg/kg), but not by the 5HT2 antagonist ketanserin (0.1 mg/kg). Consistent with these findings, salvinorin and κ-agonists (e.g., U69,593) produce effects in the unconditioned endpoints (e.g., ptosis), whereas psilocybin was inactive. Conclusions: These findings support the conclusion that the interoceptive/discriminative cue produced by salvinorin A is mediated by agonism at κ-receptors and is mechanistically distinct from that produced by a classic serotonergic hallucinogen.