The Molecular Mechanisms of Cellular Tolerance to δ-Opioid Agonists

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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.

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Correspondence to Eva V. Varga.

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Dedicated to Professor Maria Wollemann on the occasion of her 80th birthday.

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Varga, E.V. The Molecular Mechanisms of Cellular Tolerance to δ-Opioid Agonists. BIOLOGIA FUTURA 54, 203–218 (2003). https://doi.org/10.1556/ABiol.54.2003.2.9

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Keywords

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