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 desensitization mechanisms, resulting in MOR and DOR 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 6β-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.
- Received February 16, 2016.
- Accepted September 21, 2016.
This work was supported by US Public Health Service grants from the National Institutes of Health National Institute of Drug Abuse [Grant RO1 DA 024865] and National Institute of General Medical Sciences [Grant R01 GM 106035]; the William and Ella Owens Medical Research Foundation; and US Public Health Service training grants from the National Institute of Dental and Craniofacial Research [COSTAR Training Grant T32 DE 14318] and the National Institute on Drug Abuse [Grant T32 DA 031115] to L.C.S.
Portions of this work (naloxone induction of opioid receptor functional competence) were previously presented at the Annual Meeting of the Society for Neuroscience; Washington DC, November 12-16, 2011.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics