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Acta Biologica Hungarica

, Volume 54, Issue 2, pp 203–218 | Cite as

The Molecular Mechanisms of Cellular Tolerance to δ-Opioid Agonists

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  • Eva V. VargaEmail author
Article

Abstract

Chronic treatment with δ-opioid agonists, similar to other agonist drugs, causes tolerance. Tolerance is a complex adaptation process that consists of multiple, cellular and neural-system adaptations. Cellular tolerance to δ-opioid agonists involves feedback-regulation of the function, concentration, and localization of the δ-opioid receptors (receptor desensitization) as well as of intracellular effectors (functional desensitization). We are using a recombinant Chinese hamster ovary cell line expressing the human δ-opioid receptors (hDOR/CHO) to investigate the molecular mechanisms of cellular tolerance We found that the structurally distinct δ-opioid agonists mediate receptor down-regulation by different mechanisms. Thus, truncation of the last 35 C-terminal amino acids of the hDOR completely abolished DPDPE, but not SNC 80-mediated receptor down-regulation. In addition, down-regulation of the wild type-, and the truncated hDORs exhibited different inhibitor sensitivity-profile. Chronic δ-opioid agonist treatment also causes functional desensitization of forskolin-stimulated cAMP formation and cAMP overshoot in the hDOR/CHO cells. We have demonstrated that chronic SNC 80 treatment also causes concurrent phosphorylation of the adenylyl cyclase (AC) VI isoenzyme hDOR/CHO cells. Both AC superactivation and AC VI phosphorylation were SNC 80 dose-dependent, naltrindole-sensitive, and exhibited similar time course-, and protein kinase inhibitor-sensitivity profile. We hypothesize that phosphorylation of AC VI plays an important role in δ-opioid agonist-mediated AC superactivation in hDOR/CHO cells.

Keywords

Human δ-opioid receptor cellular tolerance receptor down-regulation adenylyl cyclase superactivation adenylyl cyclase phosphorylation 

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© Akadémiai Kiadó, Budapest 2003

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Authors and Affiliations

  1. 1.Department of Pharmacology and the Sarver Heart CenterThe University of Arizona, Health Sciences CenterTucsonUSA

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