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.