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The molecular mechanisms of cellular tolerance to delta-opioid agonists. A minireview

Eva V Varga1

  • 1Department of Pharmacology, Sarver Heart Center, The University of Arizona, Tucson, Arizona, USA. evarga@email.arizona.edu

Acta Biologica Hungarica
|October 11, 2003
PubMed

Insights

Chronic delta-opioid agonist use causes tolerance through cellular adaptations. Distinct agonists trigger different receptor down-regulation pathways, impacting cellular signaling and adenylyl cyclase activity.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Neuroscience

Background:

  • Chronic administration of delta-opioid agonists leads to tolerance, a complex adaptive response involving cellular and neural system changes.
  • Cellular tolerance encompasses receptor desensitization (altered function, concentration, localization) and functional desensitization of intracellular effectors.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying cellular tolerance to delta-opioid agonists.
  • To elucidate the differential effects of structurally distinct agonists on delta-opioid receptor (hDOR) regulation and downstream signaling.

Main Methods:

  • Utilized a recombinant Chinese hamster ovary (hDOR/CHO) cell line expressing human delta-opioid receptors.
  • Analyzed receptor down-regulation mechanisms in response to different delta-opioid agonists (DPDPE, SNC 80).
  • Assessed functional desensitization of forskolin-stimulated cAMP formation and adenylyl cyclase (AC) VI phosphorylation.

Main Results:

  • Structurally distinct delta-opioid agonists mediate hDOR down-regulation via different mechanisms; C-terminal truncation affected DPDPE but not SNC 80.
  • Down-regulation of wild-type and truncated hDORs exhibited differential inhibitor sensitivity.
  • Chronic SNC 80 treatment induced functional desensitization, cAMP overshoot, and concurrent phosphorylation of AC VI, which was dose-dependent and naltrindole-sensitive.

Conclusions:

  • Delta-opioid receptor down-regulation pathways are agonist-specific.
  • Phosphorylation of adenylyl cyclase VI is implicated in delta-opioid agonist-induced adenylyl cyclase superactivation.
  • These findings provide molecular insights into the cellular adaptations driving delta-opioid tolerance.

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