title: Opioid peptide receptor studies. 10. Nor-BNI differentially inhibits kappa receptor agonist-induced G-protein activation in the guinea pig caudate: further evidence of kappa receptor heterogeneity.
abstract: There is strong evidence supporting the existence of multiple kappa receptors. Previous studies proposed that U69,593 and (+)-tifluadom act on different kappa receptor subtypes, kappa(1) (kappa(1)) and kappa(2) (kappa(2)), respectively. In this study, we investigated the effects of the kappa selective antagonist nor-binaltorphimine (Nor-BNI) on U69,593- and (+)-tifluadom-induced receptor-mediated stimulation of [(35)S]-GTP-gamma-S binding in the guinea pig caudate. The IC(50) value of Nor-BNI in the presence of a stimulating concentration of U69,593 (1 microM) was 0.19+/-0.02; while the IC(50) for Nor-BNI in the presence of (+)-tifluadom (1 microM) was 13.9+/- 1.62 nM. The mu-opioid receptor antagonist CTAP (10,000 nM) significantly reduced (+)-tifluadom-stimulated [(35)S]-GTP-gamma-S binding in rat brain sections and guinea pig brain membranes, indicating that (+)-tifluadom has mu agonist activity. Under conditions in which the mu agonist activity of (+)-tifluadom was blocked by 1000 nM CTAP the Ki value for Nor-BNI for inhibition of U69,593-stimulated [(35)S]-GTP-gamma-S binding was 0.036+/-.004 nM, whereas, its Ki value for the (+)-tifluadom-stimulated [(35)S]-GTP-gamma-S binding was 0.27+/-.015 nM. These results suggest that (+)-tifluadom and U69,593 activate pharmacologically different receptors. This study provides functional evidence in support of kappa receptor heterogeneity.
authors.affiliation: Clinical Psychopharmacology Section, Division of Intramural Research, National Institute on Drug Abuse, National Institutes of Health, P. O. Box 5180, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
authors.forename: S O
authors.initials: SO
authors.lastname: Heyliger
authors.forename: C
authors.initials: C
authors.lastname: Jackson
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
mesh_terms: D000818:Animals; D044482:Benzeneacetamides; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013004:Somatostatin
chemical_list: D044482:Benzeneacetamides; C529311:CTAP octapeptide; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C116587:kappa(1) opioid receptor; C108819:kappa(2) opioid receptor; C092721:tyrosyl-tetrahydroisoquinolinecarbonyl-psi(methylamino)phenylalanyl-phenylalanine; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D001569:Benzodiazepines; C051844:norbinaltorphimine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013004:Somatostatin; D009271:Naltrexone; D019204:GTP-Binding Proteins; C045444:U 69593; C035470:tifluadom