Competition between Gi/o‐coupled receptors prevents cAMP overshoot following chronic opioid treatment

Abstract

Use of selective agonists for Gi/o‐coupled receptors endogenously expressed in SH‐SY5Y cells has revealed near complete competition for shared adenylyl cyclase (AC) enzymes, indicating a lack of specific receptor/effector pairs. For example, AC inhibition by the mu opioid agonist DAMGO was not enhanced by addition of agonists to ORL‐1, alpha 2‐adrenergic, cannabinoid or 5‐HT1A receptors. Chronic treatment with an opioid agonist leads to sensitization of AC, so that withdrawal of the agonist and stimulation of AC results in cAMP overshoot. The cAMP overshoot produced by chronic DAMGO treatment was not enhanced when combined chronically with the delta agonist DPDPE, indicating that mu and delta receptors still share AC during chronic treatment. Since opioid and other receptors share AC, cAMP overshoot following chronic opioid treatment should be prevented by heterologous inhibition of cAMP using an agonist to a different Gi/o‐coupled receptor. Indeed, mu opioid overshoot was prevented when agonists to delta opioid, ORL‐1 and alpha 2‐adrenergic receptors were added during withdrawal. Alternatively, delta opioid overshoot was prevented by the mu agonist DAMGO. In contrast, chronic incubation with a mu or delta receptor agonist did not produce heterologous tolerance, confirming that the development of tolerance is a receptor specific effect. Supported by DA23339, GM07767, DA04087.