This study focused on the in vivo effects of the -opioid hallucinogen salvinorin A, derived from the plant Salvia divinorum. The effects of salvinorin A (0.0032-0.056 mg/kg i.v.) were studied in a neuroendocrine biomarker assay of the anterior pituitary hormone prolactin in gonadally intact, adult male and female rhesus monkeys (n ϭ 4 each). Salvinorin A produced dose-and time-dependent neuroendocrine effects, similar to the synthetic high-efficacy -agonist U69,593but of shorter duration than the latter. Salvinorin A was approximately equipotent to U69,593 in this endpoint (salvinorin A ED 50 , 0.015 mg/kg; U69,593 ED 50 , 0.0098 mg/kg). The effects of i.v. salvinorin A were not prevented by a small dose of the opioid antagonist nalmefene (0.01 mg/kg s.c.) but were prevented by a larger dose of nalmefene (0.1 mg/kg); the latter nalmefene dose is sufficient to produce -antagonist effects in this species. In contrast, the 5HT2 receptor antagonist ketanserin (0.1 mg/kg i.m.) did not prevent the effects of salvinorin A. As expected, the neuroendocrine effects of salvinorin A (0.0032 mg/kg i.v.) were more robust in female than in male subjects. Related studies focused on full-length cloning of the coding region of the rhesus monkey -opioid receptor (OPRK1) gene and revealed a high homology of the nonhuman primate OPRK1 gene compared with the human OPRK1 gene, including particular C-terminal residues thought to be involved in receptor desensitization and internalization. The present studies indicate that the hallucinogen salvinorin A acts as a high-efficacy -agonist in nonhuman primates in a translationally viable neuroendocrine biomarker assay.

SummaryThe in vivo pharmacodynamics of the opioid neuropeptide β-endorphin (a major endogenous agonist at the μ-opioid receptor) are difficult to determine in non human primate models with translational value, or in humans. The present studies therefore employed a neuroendocrine biomarker assay, prolactin release, to systematically compare the in vivo profile of i.v. β-endorphin (0.01-0.32 mg/ kg; i.v.) in gonadally intact male rhesus monkeys (n=4) to that of the peripherally selective μ-agonist loperamide (0.01-0.32 mg/kg; i.v.) and the centrally-penetrating μ-agonist fentanyl (0.0056-0.018 mg/kg; i.v.). Studies utilized a standardized time course design (measuring prolactin levels 5-120 min after agonist administration).β-endorphin displayed only limited effectiveness in causing prolactin release when tested over this 30-fold dose range, compared to loperamide or fentanyl. Furthermore, two of the four subjects were only minimally responsive to β-endorphin. This differential responsiveness was not due to the presence of a previously described single nucleotide polymorphism at the OPRM1 gene (C77G), known to affect β-endorphin pharmacodynamics in vitro. In vivo biotransformation studies with MALDI mass spectrometry determined that full length β-endorphin was detectable in all subjects up to at least 5 min after i.v. administration. Thus, the relative ineffectiveness of i.v. β-endorphin in this assay does not appear to be principally due to rapid generation of non-opioid fragments of this neuropeptide.