title: Kappa opioid mediation of cannabinoid effects of the potent hallucinogen, salvinorin A, in rodents.
abstract: BACKGROUND
  Salvinorin A, the primary psychoactive derivative of the hallucinogenic herb Salvia divinorum, is a potent and highly selective kappa-opioid receptor (KOR) agonist. Several recent studies, however, have suggested endocannabinoid system mediation of some of its effects.
  
  
  OBJECTIVE
  This study represents a systematic examination of this hypothesis.
  
  
  METHODS
  Salvinorin A was isolated from S. divinorum and was evaluated in a battery of in vitro and in vivo procedures designed to detect cannabinoid activity, including CB(1) receptor radioligand and [(35)S]GTPgammaS binding, calcium flux assay, in vivo cannabinoid screening tests, and drug discrimination.
  
  
  RESULTS
  Salvinorin A did not bind to nor activate CB(1) receptors. In vivo salvinorin A produced pronounced hypolocomotion and antinociception (and to a lesser extent, hypothermia). These effects were blocked by the selective KOR antagonist, JDTic, but not by the CB(1) receptor antagonist rimonabant. Interestingly, however, rimonabant attenuated KOR activation stimulated by U69,593 in a [(35)S]GTPgammaS assay. Salvinorin A did not substitute for Delta(9)-tetrahydrocannabinol (THC) in mice trained to discriminate THC.
  
  
  CONCLUSIONS
  These findings suggest that similarities in the pharmacological effects of salvinorin A and those of cannabinoids are mediated by its activation of KOR rather than by any direct action of salvinorin A on the endocannabinoid system. Further, the results suggest that rimonabant reversal of salvinorin A effects in previous studies may be explained in part by rimonabant attenuation of KOR activation.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298-0613, USA.
authors.forename: D Matthew
authors.initials: DM
authors.lastname: Walentiny
authors.forename: Robert E
authors.initials: RE
authors.lastname: Vann
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Warner
authors.forename: Lindsey S
authors.initials: LS
authors.lastname: King
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Seltzman
authors.forename: Hernán A
authors.initials: HA
authors.lastname: Navarro
authors.forename: Charles E
authors.initials: CE
authors.lastname: Twine
authors.forename: Brian F
authors.initials: BF
authors.lastname: Thomas
authors.forename: Anne F
authors.initials: AF
authors.lastname: Gilliam
authors.forename: Brian P
authors.initials: BP
authors.lastname: Gilmour
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000502:physiology; D004193:Discrimination Learning; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D013759:Dronabinol / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D010147:Pain Measurement; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011869:Radioligand Assay; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D027544:Salvia; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
chemical_list: C433814:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide; D063385:Cannabinoid Receptor Modulators; D045785:Diterpenes, Clerodane; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D017473:Receptors, Opioid, kappa; D044005:Tetrahydroisoquinolines; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013759:Dronabinol; D000077285:Rimonabant; D002118:Calcium; C090499:salvinorin A