The Plant-derived Hallucinogen, Salvinorin A, Produces Kappa-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; s.c.) from vehicle in a food-reinforced FR20 (fixed ratio 20) operant conditioning procedure (n=3). The ability of salvinorin A to cause generalization (> or =90% 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.