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Reciprocal Regulation of Agonist and Inverse Agonist Signaling Efficacy upon Short-Term Treatment of the Human -Opioid Receptor with an Inverse Agonist

Département de Biochimie (G.P., M.A., M.B.) and Département de Pharmacologie (A.D.), Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada; and Institut de Recherches Cliniques de Montréal (P.W.S.), Université de Montréal, Montréal, Québec, Canada

Rapid regulation of receptor signaling by agonist ligands is widely accepted, whereas short-term adaptation to inverse agonists has been little documented. In the present study, guanosine 5'-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPS) binding and cAMP accumulation assays were used to assess the consequences of 30-min exposure to the inverse agonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI174864) (1 µM) on -opioid receptor signaling efficacy. ICI174864 pretreatment increased maximal effect (E_max) for the partial agonist Tyr-1,2,3,4-tetrahydroisoquinoline-Phe-Phe-OH (TIPP) at the two levels of the signaling cascade, whereas E_max values for more efficacious agonists like (+)-4-[(R)--((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80) and bremazocine were increased in [³⁵S]GTPS binding but not in cAMP accumulation assays. Pre-exposure to ICI174864 also induced a shift to the left in dose-response curves for bremazocine and TIPP. On the other hand, E_max for the inverse agonist H-Tyr-Tic[CH₂NH]Cha-Phe-OH was reduced in both assays, but no changes in potency were observed. For the weaker inverse agonist naloxone, E_max in [³⁵S]GTPS binding was drastically modified because the drug turned from inverse agonist to agonist after ICI174864 pretreatment. Likewise, ICI174864 turned from inverse agonist to agonist when tested in cAMP accumulation assays. In both cases, inversion of efficacy was concomitant with marked increase in potency for agonist effects. Together with functional changes, short-term treatment with ICI174864 reduced basal receptor phosphorylation and increased immunoreactivity for G_i3 in membrane preparations. Functional consequences of ICI174864 pretreatment were simulated in the cubic ternary complex model by increasing receptor/G protein coupling or G protein amount available for interaction with the receptor. Taken together, these data show that inverse agonists may induce rapid regulation in receptor signaling efficacy.

Address correspondence to: Dr. Graciela Piñeyro, 7331 Rue Hochelaga, Centre de Recherche Fernand Séguin, Montréal, Québec, H1N 3V2 Canada. E-mail: graciela.pineyro{at}crfs.umontreal.ca

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