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

J Pharmacol Exp Ther. 2007 Jan;320(1):300-6. doi: 10.1124/jpet.106.112417. Epub 2006 Oct 23.


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

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Benzeneacetamides / pharmacology
  • Biomarkers
  • Cloning, Molecular
  • Diterpenes / pharmacology*
  • Diterpenes, Clerodane
  • Female
  • Hallucinogens / pharmacology*
  • Humans
  • Macaca mulatta
  • Male
  • Molecular Sequence Data
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Prolactin / blood*
  • Pyrrolidines / pharmacology
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / chemistry
  • Receptors, Opioid, kappa / genetics*
  • Sex Characteristics


  • Benzeneacetamides
  • Biomarkers
  • Diterpenes
  • Diterpenes, Clerodane
  • Hallucinogens
  • OPRK1 protein, human
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • Naltrexone
  • Prolactin
  • U 69593
  • salvinorin A
  • nalmefene