Opioid peptide receptor studies. 10. Nor-BNI differentially inhibits kappareceptor agonist-induced G-protein activation in the guinea pig caudate: Further evidence of kappa receptor heterogeneity

There is strong evidence supporting the existence of multiple kappa recepto rs. Previous studies proposed that U69,593 and (+)-tifluadom act on differe nt kappa receptor subtypes, kappa(1) (kappa(1)) and kappa(2) (kappa(2)), re spectively. In this study, we investigated the effects of the kappa selecti ve antagonist nor-binaltorphimine (Nor-BNI) on U69,593- and (+)-tifluadom-i nduced receptor-mediated stimulation of [S-35]-GTP-gamma-S binding in the g uinea pig caudate. The IC50 value of Nor-BNI in the presence of a stimulati ng concentration of U69,593 (1 mu M) was 0.19 +/- 0.02; while the IC50 for Nor-BNI in the presence of (+)-tifluadom (1 mu M) was 13.9 +/- 1.62 nM. The mu-opioid receptor antagonist CTAP (10,000 nM) significantly reduced (+)-t ifluadom-stimulated [S-35]-GTP-gamma-S binding in rat brain sections and gu inea pig brain membranes, indicating that (+)-tifluadom has mu agonist acti vity. 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 [S-35]-GTP-gamma-S binding was 0.036 +/- .004 nM, whereas, its Ki value for the (+)-tifluadom-stimulated [S-35]-GTP-gamma-S binding was 0. 27 +/- .015 nM. These results suggest that (+)-tifluadom and U69,593 activa te pharmacologically different receptors. This study provides functional ev idence in support of kappa receptor heterogeneity. Published 1999 Wiley-Lis s, Inc.