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Vol. 60, Issue 4, 816-827, October 2001

Short-Term Inverse-Agonist Treatment Induces Reciprocal Changes in delta -Opioid Agonist and Inverse-Agonist Binding Capacity

Graciela Piñeyro, Mounia Azzi, André De Léan, Peter Schiller, and Michel Bouvier

Département de Biochimie (G.P., M.A., M.B.), Pharmacologie (A.D.L.), and Institut des Recherches Cliniques de Montréal (P.S.), Université de Montréal, Montréal, Canada

This study assessed the effects of short-term treatment (30-min) with inverse agonists on receptor protein levels and on the ability of agonists, inverse agonists, and neutral antagonists to bind to the human delta -opioid receptor (hdelta OR). Incubation of human embryonic kidney 293s cells stably expressing hdelta OR with the inverse agonist ICI174864 (1 µM) induced reciprocal changes in agonist and inverse-agonist binding. The total number of binding sites recognized by the agonists [3H]bremazocine and [3H][D-Pen2,D-Pen5]-enkephalin was reduced by 33 and 57%, respectively, whereas binding capacity for the radiolabeled inverse-agonist [3H]Tyr-TicY[CH2NH]Cha-Phe-OH increased by 44%. In contrast, total receptor protein and sites labeled by neutral antagonists [3H]naltrindole and [3H]Tyr-D-Tic-Phe-Phe-OH remained unchanged. Pertussis toxin (PTX) and 5-guanylylimidodiphosphate (GppNHp) mimicked the outcome of ICI174864 pretreatment in promoting the loss of agonist binding sites. The lack of an additive effect on [3H]bremazocine binding when these three agents were combined indicates that inverse agonists may, in part, share the mechanism by which GppNHp and PTX reduce agonist binding capacity. Spontaneous recovery of maximal agonist binding capacity after inverse-agonist treatment was slow, suggesting a decrease in the isomerization rate between agonist- and inverse agonist-preferring conformations. Overall, the data presented are consistent with the idea that hdelta ORs exist in multiple states capable of discriminating among ligands of different levels of efficacy and show that, after short-term treatment with an inverse agonist, the receptor ability to adopt conformations preferentially induced by agonist ligands is reduced.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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