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
✍ Scribed by Simone O. Heyliger; Chris Jackson; Kenner C. Rice; Richard B. Rothman
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 215 KB
- Volume
- 34
- Category
- Article
- ISSN
- 0887-4476
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✦ Synopsis
There is strong evidence supporting the existence of multiple kappa receptors. Previous studies proposed that U69,593 and (ϩ)-tifluadom act on different kappa receptor subtypes, kappa 1 ( 1 ) and kappa 2 ( 2 ), respectively. In this study, we investigated the effects of the kappa selective antagonist nor-binaltorphimine (Nor-BNI) on U69,593-and (ϩ)-tifluadom-induced receptor-mediated stimulation of [ 35 S]-GTP-␥-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 µM) was 0.19 Ϯ 0.02; while the IC 50 for Nor-BNI in the presence of (ϩ)-tifluadom (1 µM) was 13.9 Ϯ 1.62 nM. The mu-opioid receptor antagonist CTAP (10,000 nM) significantly reduced (ϩ)-tifluadom-stimulated [ 35 S]-GTP-␥-S binding in rat brain sections and guinea pig brain membranes, indicating that (ϩ)-tifluadom has mu agonist activity. Under conditions in which the mu agonist activity of (ϩ)-tifluadom was blocked by 1000 nM CTAP the Ki value for Nor-BNI for inhibition of U69,593-stimulated [ 35 S]-GTP-␥-S binding was 0.036 Ϯ .004 nM, whereas, its Ki value for the (ϩ)-tifluadom-stimulated [ 35 S]-GTP-␥-S binding was 0.27 Ϯ .015 nM. These results suggest that (ϩ)-tifluadom and U69,593 activate pharmacologically different receptors. This study provides functional evidence in support of kappa receptor heterogeneity.