The plant-derived hallucinogen, salvinorin A, produces κ-opioid agonist-like discriminative effects in rhesus monkeys

Rationale. Salvinorin A is the active component of the hallucinogenic plant Salvia divinorum. The potential mode of action of this hallucinogen was unknown until recently. A recent in vitro study detected high affinity and efficacy of salvinorin A at kappa-opioid receptors. It was postulated that salvinorin A would produce discriminative stimulus effects similar to those of a high efficacy kappa-agonist (U69,593) in rhesus monkeys. Methods. Monkeys were previously trained to discriminate U69,593 (0.0056 or 0.013 mg/kg; SC) from vehicle in a food-reinforced FR20 (fixed ratio 20) operant conditioning procedure (n=3). The ability of salvinorin A to cause generalization (greater than or equal to90% U69,593-appropriate responding) was examined in time course and cumulative dose-effect curve studies. Results. All subjects dose-dependently emitted full U69,593-appropriate responding after salvinorin A (0.001-0.032 mg/kg, SC). Salvinorin A-induced generalization started 5-15 min after injection, and dissipated by 120 min. The opioid antagonist quadazocine (0.32 mg/kg) fully blocked the effects of salvinorin A. The kappa-selective antagonist GNTI (1 mg/kg; 24 h pretreatment) did not cause significant antagonism of the effects of salvinorin A (GNTI, under these conditions, was only effective as an antagonist in two of three monkeys). The NMDA antagonist ketamine (0.1-3.2 mg/kg) was not generalized by any subject, indicating that not all compounds that produce hallucinogenic or psychotomimetic effects in humans are generalized by subjects trained to discriminate U69,593. Conclusions. The naturally occurring hallucinogen salvinorin A produces discriminative stimulus effects similar to those of a high efficacy kappa-agonist in non-human primates.