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Pannexin-1 channel inhibition alleviates opioid withdrawal in rodents by modulating locus coeruleus to spinal cord circuitry

Author

Listed:
  • Charlie H. T. Kwok

    (University of Calgary
    University of Calgary)

  • Erika K. Harding

    (University of Calgary
    University of Calgary
    University of Calgary)

  • Nicole E. Burma

    (University of Calgary
    University of Calgary)

  • Tamara Markovic

    (Washington University Pain Center)

  • Nicolas Massaly

    (Washington University Pain Center
    University of California Los Angeles)

  • Nynke J. van den Hoogen

    (University of Calgary
    University of Calgary)

  • Sierra Stokes-Heck

    (University of Calgary
    University of Calgary)

  • Eder Gambeta

    (University of Calgary)

  • Kristina Komarek

    (University of Calgary
    University of Calgary)

  • Hye Jean Yoon

    (Washington University Pain Center)

  • Kathleen E. Navis

    (University of Calgary)

  • Brendan B. McAllister

    (University of Calgary
    University of Calgary)

  • Julia Canet-Pons

    (University of Calgary
    University of Calgary)

  • Churmy Fan

    (University of Calgary
    University of Calgary)

  • Rebecca Dalgarno

    (University of Calgary
    University of Calgary)

  • Evgueni Gorobets

    (University of Calgary)

  • James W. Papatzimas

    (University of Calgary)

  • Zizhen Zhang

    (University of Calgary)

  • Yuta Kohro

    (University of Calgary
    University of Calgary)

  • Connor L. Anderson

    (University of Calgary)

  • Roger J. Thompson

    (University of Calgary)

  • Darren J. Derksen

    (University of Calgary)

  • Jose A. Morón

    (Washington University Pain Center)

  • Gerald W. Zamponi

    (University of Calgary)

  • Tuan Trang

    (University of Calgary
    University of Calgary)

Abstract

Opioid withdrawal is a liability of chronic opioid use and misuse, impacting people who use prescription or illicit opioids. Hyperactive autonomic output underlies many of the aversive withdrawal symptoms that make it difficult to discontinue chronic opioid use. The locus coeruleus (LC) is an important autonomic centre within the brain with a poorly defined role in opioid withdrawal. We show here that pannexin-1 (Panx1) channels expressed on microglia critically modulate LC activity during opioid withdrawal. Within the LC, we found that spinally projecting tyrosine hydroxylase (TH)-positive neurons (LCspinal) are hyperexcitable during morphine withdrawal, elevating cerebrospinal fluid (CSF) levels of norepinephrine. Pharmacological and chemogenetic silencing of LCspinal neurons or genetic ablation of Panx1 in microglia blunted CSF NE release, reduced LC neuron hyperexcitability, and concomitantly decreased opioid withdrawal behaviours in mice. Using probenecid as an initial lead compound, we designed a compound (EG-2184) with greater potency in blocking Panx1. Treatment with EG-2184 significantly reduced both the physical signs and conditioned place aversion caused by opioid withdrawal in mice, as well as suppressed cue-induced reinstatement of opioid seeking in rats. Together, these findings demonstrate that microglial Panx1 channels modulate LC noradrenergic circuitry during opioid withdrawal and reinstatement. Blocking Panx1 to dampen LC hyperexcitability may therefore provide a therapeutic strategy for alleviating the physical and aversive components of opioid withdrawal.

Suggested Citation

  • Charlie H. T. Kwok & Erika K. Harding & Nicole E. Burma & Tamara Markovic & Nicolas Massaly & Nynke J. van den Hoogen & Sierra Stokes-Heck & Eder Gambeta & Kristina Komarek & Hye Jean Yoon & Kathleen , 2024. "Pannexin-1 channel inhibition alleviates opioid withdrawal in rodents by modulating locus coeruleus to spinal cord circuitry," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50657-7
    DOI: 10.1038/s41467-024-50657-7
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    References listed on IDEAS

    as
    1. J. M. Delfs & Y. Zhu & J. P. Druhan & G. Aston-Jones, 2000. "Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion," Nature, Nature, vol. 403(6768), pages 430-434, January.
    2. Yingjie Zhu & Carl F. R. Wienecke & Gregory Nachtrab & Xiaoke Chen, 2016. "A thalamic input to the nucleus accumbens mediates opiate dependence," Nature, Nature, vol. 530(7589), pages 219-222, February.
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