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

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 E. Navis, Brendan B. McAllister, Julia Canet-Pons, Churmy Fan, Rebecca Dalgarno, Evgueni Gorobets, James W. Papatzimas, Zizhen Zhang, Yuta Kohro, Connor L. Anderson, Roger J. Thompson, Darren J. Derksen, Jose A. Morón, Gerald W. Zamponi and Tuan Trang ()
Additional contact information
Charlie H. T. Kwok: University of Calgary
Erika K. Harding: University of Calgary
Nicole E. Burma: University of Calgary
Tamara Markovic: Washington University Pain Center
Nicolas Massaly: Washington University Pain Center
Nynke J. van den Hoogen: University of Calgary
Sierra Stokes-Heck: University of Calgary
Eder Gambeta: University of Calgary
Kristina Komarek: University of Calgary
Hye Jean Yoon: Washington University Pain Center
Kathleen E. Navis: University of Calgary
Brendan B. McAllister: University of Calgary
Julia Canet-Pons: University of Calgary
Churmy Fan: University of Calgary
Rebecca Dalgarno: University of Calgary
Evgueni Gorobets: University of Calgary
James W. Papatzimas: University of Calgary
Zizhen Zhang: University of Calgary
Yuta Kohro: 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

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50657-7

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