Mu-opioid receptors in nociceptive afferents produce a sustained suppression of hyperalgesia in chronic pain.

TitleMu-opioid receptors in nociceptive afferents produce a sustained suppression of hyperalgesia in chronic pain.
Publication TypeJournal Article
Year of Publication2018
AuthorsSeverino A, Chen W, Hakimian JK, Kieffer BL, Gaveriaux-Ruff C, Walwyn W, Marvizon JCarlos
JournalPain
Date Published2018 Apr 17
ISSN1872-6623
Abstract

The latent sensitization model of chronic pain reveals that recovery from some types of long-term hyperalgesia is an altered state in which nociceptive sensitization persists but is suppressed by the ongoing activity of analgesic receptors such as µ-opioid receptors (MORs). To determine whether these MORs are the ones present in nociceptive afferents, we bred mice expressing Cre-recombinase under the Nav1.8 channel promoter (Nav1.8cre) with MOR-floxed mice (flMOR). These Nav1.8cre/flMOR mice had reduced MOR expression in primary afferents, as revealed by quantitative PCR, in situ hybridization and immunofluorescence colocalization with the neuropeptide CGRP. We then studied the recovery from chronic pain of these mice and their flMOR littermates. When Nav1.8cre/flMOR mice were injected in the paw with complete Freund's adjuvant they developed mechanical hyperalgesia that persisted for over two months, whereas the responses of flMOR mice returned to baseline after three weeks. We then used the inverse agonist naltrexone to assess ongoing MOR activity. Naltrexone produced a robust reinstatement of hyperalgesia in control flMOR mice, but produced no effect in the Nav1.8/flMOR males and a weak reinstatement of hyperalgesia in Nav1.8/flMOR females. Naltrexone also reinstated swelling of the hind paw in flMOR mice and female Nav1.8cre/flMOR mice, but not male Nav1.8cre/flMOR mice. The MOR agonist DAMGO inhibited substance P release in flMOR mice but not Nav1.8cre/flMOR mice, demonstrating a loss of MOR function at the central terminals of primary afferents. We conclude that MORs in nociceptive afferents mediate an ongoing suppression of hyperalgesia to produce remission from chronic pain.

DOI10.1097/j.pain.0000000000001247
Alternate JournalPain
PubMed ID29677019
Grant ListP30 DK041301 / DK / NIDDK NIH HHS / United States
R01 DA033059 / DA / NIDA NIH HHS / United States

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