Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans.
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.
Butelman
Eduardo R
ER
Laboratory on the Biology of Addictive Diseases, The Rockefeller University, Box 171, 1230 York Avenue, New York NY 10021, USA. butelme@mail.rockefeller.edu
Mandau
Marek
M
Tidgewell
Kevin
K
Prisinzano
Thomas E
TE
Yuferov
Vadim
V
Kreek
Mary Jeanne
MJ
D000595:Amino Acid Sequence; D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology; D015415:Biomarkers; D003001:Cloning, Molecular; D004224:Diterpenes / Q000494:pharmacology*; D045785:Diterpenes, Clerodane; D005260:Female; D006213:Hallucinogens / Q000494:pharmacology*; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D011388:Prolactin / Q000097:blood*; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000737:chemistry / Q000235:genetics*; D012727:Sex Characteristics
D044482:Benzeneacetamides; D015415:Biomarkers; D004224:Diterpenes; D045785:Diterpenes, Clerodane; D006213:Hallucinogens; C515653:OPRK1 protein, human; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D009271:Naltrexone; D011388:Prolactin; C045444:U 69593; C090499:salvinorin A; C038981:nalmefene