title: Unconditioned behavioral effects of the powerful kappa-opioid hallucinogen salvinorin A in nonhuman primates: fast onset and entry into cerebrospinal fluid.
abstract: Salvinorin A is the main active component of the widely available hallucinogenic plant, Salvia divinorum. Salvinorin A is a selective high-efficacy kappa-agonist in vitro, with some unique pharmacodynamic properties. Descriptive reports show that salvinorin A-containing products produce robust behavioral effects in humans. However, these effects have not been systematically characterized in human or nonhuman primates to date. Therefore, the present studies focused on the characterization of overt effects of salvinorin A, such as sedation (operationally defined as unresponsiveness to environmental stimuli) and postural relaxation, previously observed with centrally penetrating kappa-agonists in nonhuman primates. Salvinorin A was active in these endpoints (dose range, 0.01-0.1 mg/kg i.v.) in nonhuman primates (n = 3-5), similar to the synthetic kappa-agonist U69,593 [(+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]-dec-8-yl]-benzeneacetamide], used for comparison herein. Salvinorin A effects could be prevented by a clinically available opioid antagonist, nalmefene (0.1 mg/kg), at doses known to block kappa-receptor-mediated effects in nonhuman primates. When injected intravenously, salvinorin A (0.032 mg/kg) could enter the central nervous system (as reflected in cisternal cerebrospinal fluid) within 1 min and reach concentrations that are in the reported range of the affinity (K(i)) of this ligand for brain kappa-receptors. Consistent with this finding, specific translationally viable behavioral effects (e.g., facial relaxation and ptosis) could also be detected within 1 to 2 min of injection of salvinorin A. These are the first studies documenting rapid unconditioned effects of salvinorin A in a primate species, consistent with descriptive reports of rapid and robust effects of this powerful hallucinogen in humans.
authors.affiliation: Laboratory on the Biology of Addictive Diseases, Rockefeller University (Box 171), 1230 York Ave., New York, NY 1006, USA. butelme@rockefeller.edu
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Butelman
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
authors.forename: Szymon
authors.initials: S
authors.lastname: Rus
authors.forename: Mary Jeanne
authors.initials: MJ
authors.lastname: Kreek
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D045785:Diterpenes, Clerodane / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D008253:Macaca mulatta; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000502:physiology; D027544:Salvia
chemical_list: D045785:Diterpenes, Clerodane; D006213:Hallucinogens; D017473:Receptors, Opioid, kappa; C090499:salvinorin A