Salvia divinorum is a hallucinogenic plant used by the Mazatec Indians of Mexico for traditional spiritual ceremonies. The active constituent, salvinorin A, induces profound hallucinations, however the biological mechanism for this action is not known. Affinity-binding studies suggest that the biologic activity of salvinorin A involves the kappa-opioid receptor. The purpose of this study was to evaluate the antinociceptive effect of salvinorin A in mice. Salvinorin A and opioid receptor antagonists were administered intrathecally and the tail-flick latencies were used as a measure of antinociception. Salvinorin A increased tail-flick latencies in a dose-dependent manner (13.9-23.1 nmol) compared to control trials. Pretreatment with the kappa-opioid receptor antagonist nor-binaltorphimine attenuated the salvinorin A induced increase in tail-flick latency. In contrast, neither the mu-opioid receptor antagonist beta-funaltrexamine nor delta-opioid receptor antagonist naltrindole significantly affected the antinociceptive response of salvinorin A administration. These data support previous reports that salvinorin A represents a unique non-alkaloidal agonist for the kappa-opioid receptor.