17060493

pubmed:Citation

1

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.

eng

IM

MEDLINE

0022-3565

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NLM

300-6

pubmed-meshheading:17060493-Amino Acid Sequence, pubmed-meshheading:17060493-Animals, pubmed-meshheading:17060493-Benzeneacetamides, pubmed-meshheading:17060493-Biological Markers, pubmed-meshheading:17060493-Cloning, Molecular, pubmed-meshheading:17060493-Diterpenes, pubmed-meshheading:17060493-Diterpenes, Clerodane, pubmed-meshheading:17060493-Female, pubmed-meshheading:17060493-Hallucinogens, pubmed-meshheading:17060493-Humans, pubmed-meshheading:17060493-Macaca mulatta, pubmed-meshheading:17060493-Male, pubmed-meshheading:17060493-Molecular Sequence Data, pubmed-meshheading:17060493-Naltrexone, pubmed-meshheading:17060493-Prolactin, pubmed-meshheading:17060493-Pyrrolidines, pubmed-meshheading:17060493-Receptors, Opioid, kappa, pubmed-meshheading:17060493-Sex Characteristics

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

Journal Article, Research Support, N.I.H., Extramural