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BEHAVIORAL PHARMACOLOGY

Effects of Salvinorin A, a -Opioid Hallucinogen, on a Neuroendocrine Biomarker Assay in Nonhuman Primates with High -Receptor Homology to Humans

Laboratory on the Biology of Addictive Diseases, The Rockefeller University, New York, New York (E.R.B., M.M., V.Y., M.J.K.); and Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, Iowa (K.T., T.E.P.)

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 = 4 each). Salvinorin A produced dose- and time-dependent neuroendocrine effects, similar to the synthetic high-efficacy -agonist U69,593 ((+)-(5,7 ,8)-N-methyl-N-[7-(1-pyrrolidiniyl)-1-oxaspiro[4.5]dec-8yl]-benzeneacetamide), but of shorter duration than the latter. Salvinorin A was approximately equipotent to U69,593 in this endpoint (salvinorin A ED₅₀, 0.015 mg/kg; U69,593 ED₅₀, 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.

Address correspondence to: Dr. Eduardo R. Butelman, The Rockefeller University, Box 171, 1230 York Avenue, New York NY 10021. E-mail: butelme{at}mail.rockefeller.edu

This article has been cited by other articles:

				E. R. Butelman, T. E. Prisinzano, H. Deng, S. Rus, and M. J. Kreek Unconditioned Behavioral Effects of the Powerful {kappa}-Opioid Hallucinogen Salvinorin A in Nonhuman Primates: Fast Onset and Entry into Cerebrospinal Fluid J. Pharmacol. Exp. Ther., February 1, 2009; 328(2): 588 - 597. [Abstract] [Full Text] [PDF]

				E. R. Butelman, S. Rus, D. S. Simpson, A. Wolf, T. E. Prisinzano, and M. J. Kreek The Effects of Herkinorin, the First {micro}-Selective Ligand from a Salvinorin A-Derived Scaffold, in a Neuroendocrine Biomarker Assay in Nonhuman Primates J. Pharmacol. Exp. Ther., October 1, 2008; 327(1): 154 - 160. [Abstract] [Full Text] [PDF]

				Y. Wang, Y. Chen, W. Xu, D. Y.W. Lee, Z. Ma, S. M. Rawls, A. Cowan, and L.-Y. Liu-Chen 2-Methoxymethyl-Salvinorin B Is a Potent {kappa} Opioid Receptor Agonist with Longer Lasting Action in Vivo Than Salvinorin A J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 1073 - 1083. [Abstract] [Full Text] [PDF]