Salvinorin A is the main active component of the widely available hallucinogenic plant, Salvia divinorum. Salvinorin A is a selective high-efficacy -agonist in vitro, with some unique pharmacodynamic properties. Descriptive reports show that salvinorin A-containing products produce robust behavioral effects in humans. However, these effects have not been systematically characterized in human or nonhuman primates to date. Therefore, the present studies focused on the characterization of overt effects of salvinorin A, such as sedation (operationally defined as unresponsiveness to environmental stimuli) and postural relaxation, previously observed with centrally penetrating -agonists in nonhuman primates. Salvinorin A was active in these endpoints (dose range, 0.01-0

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.

Herkinorin is the first -opioid receptor-selective ligand from the salvinorin A diterpenoid scaffold. Herkinorin has relative Ͼ Ͼ ␦ binding selectivity, and it can act as an agonist at both -and -receptors, in vitro. These studies were the first in vivo evaluation of the effects of herkinorin in nonhuman primates, using prolactin release, a neuroendocrine biomarker assay that is responsive to both -and -agonists, as well as to compounds with limited ability to cross the blood-brain barrier. In cumulative dosing studies (0.01-0.32 mg/kg i.v.), herkinorin produced only small effects in gonadally intact males (n ϭ 4), but a more robust effect in females (n ϭ 4). Time course studies with herkinorin (0.32 mg/kg) confirmed this greater effectiveness in females and revealed a fast onset after i.v. administration (e.g., by 5-15 min). Antagonism experiments with different doses of nalmefene (0.01 and 0.1 mg/kg) caused dose-dependent and complete prevention of the effect of herkinorin in females. This is consistent with a principal -agonist effect of herkinorin, with likely partial contribution by -agonist effects. The peripherally selective antagonist quaternary naltrexone (1 mg/kg s.c.) caused approximately 70% reduction in the peak effect of herkinorin (0.32 mg/kg) in females, indicating that this effect of herkinorin is prominently mediated outside the blood-brain barrier.Salvinorin A, a plant-derived hallucinogenic diterpene, is a highly selective -opioid agonist, and a novel template for semisynthetic opioid analogs (Roth et al., 2002;Prisinzano and Rothman, 2008). One of these novel analogs is herkinorin, the first salvinorin-derived compound with -over -selectivity reported in the literature (Harding et al., 2005). Herkinorin has approximately 8-fold selectivity for -over -receptors and approximately 98-fold selectivity for -over ␦-receptors in competition binding assays (Harding et al., 2005). Herkinorin acts as a high-efficacy agonist at bothand -receptors in the guanosine 5Ј-O-(3-thio)triphosphate assay (Harding et al., 2005), with greater relative potency at -receptors. Herkinorin also displays some unique features in its interactions at the -receptor, such as decreased agonist-induced internalization (Groer et al., 2007;Xu et al., 2007).