Constitutive desensitization of opioid receptors in peripheral sensory neurons

Laura C. Sullivan, Teresa S. Chavera, Raehannah J. Jamshidi, Kelly A. Berg, William P. Clarke

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Opioid receptors expressed by peripheral pain-sensing neurons are functionally inactive for antinociceptive signaling under most basal conditions; however, tissue damage or exposure to inflammatory mediators (e.g., bradykinin) converts these receptors from a nonresponsive state to a functionally competent state. Here we tested the hypothesis that the basal, nonresponsive state of the mu- and delta-opioid receptors (MOR and DOR, respectively) is the result of constitutive receptor activity that activates desensitizationmechanisms, resulting inMOR andDOR receptor systems that are constitutively desensitized. Consistent with our previous findings, under basal conditions, neither the MOR agonist [D-Ala2, N-MePhe4,Gly-ol5]-enkephalin nor the DOR agonist [D-Pen2,5]- enkephalin, inhibited prostaglandin E2 (PGE2)-stimulated cAMP accumulation in peripheral sensory neurons in culture (ex vivo) or inhibited PGE2-stimulated thermal allodynia in the rat hind paw in vivo. Prolonged treatment with naloxone induced MOR and DOR responsiveness both in vivo and ex vivo to a similar magnitude as that produced by bradykinin. Also similar to bradykinin, the effect of naloxone persisted for 60 minutes after washout of the ligand. By contrast, prolonged treatment with 6b-naltrexol, did not induce functional competence of MOR or DOR but blocked the effect of naloxone. Treatment with siRNA for β-arrestin- 2, but not β-arrestin-1, also induced MOR and DOR functional competence in cultured peripheral sensory neurons. These data suggest that the lack of responsiveness of MOR and DOR to agonist for antinociceptive signaling in peripheral sensory neurons is due to constitutive desensitization that is likely mediated by β-arrestin-2.

Original languageEnglish (US)
Pages (from-to)411-419
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume359
Issue number3
DOIs
StatePublished - Dec 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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