Effects of salvinorin A, a κ-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high κ-receptor homology to humans

Eduardo R. Butelman, Marek Mandau, Kevin Tidgewell, Thomas E. Prisinzano, Vadim Yuferov, Mary Jeanne Kreek

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

This study focused on the in vivo effects of the κ-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 κ-agonist U69,593 ((+)-(5α,7 α,8β)-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 κ-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 κ-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 κ-agonist in nonhuman primates in a translationally viable neuroendocrine biomarker assay.

Original languageEnglish
Pages (from-to)300-306
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume320
Issue number1
DOIs
StatePublished - 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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