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

  • Nat Commun. 2024 Jul 24;15(1):6264. doi: 10.1038/s41467-024-50657-7.
Charlie H T Kwok  #  1  2 ,  Erika K Harding  #  1  2  3 ,  Nicole E Burma  #  1  2 ,  Tamara Markovic  4 ,  Nicolas Massaly  4  5 ,  Nynke J van den Hoogen  1  2 ,  Sierra Stokes-Heck  1  2 ,  Eder Gambeta  3 ,  Kristina Komarek  1  2 ,  Hye Jean Yoon  4 ,  Kathleen E Navis  6 ,  Brendan B McAllister  1  2 ,  Julia Canet-Pons  1  2 ,  Churmy Fan  1  2 ,  Rebecca Dalgarno  1  2 ,  Evgueni Gorobets  6 ,  James W Papatzimas  6 ,  Zizhen Zhang  3 ,  Yuta Kohro  1  2 ,  Connor L Anderson  7 ,  Roger J Thompson  7 ,  Darren J Derksen  6 ,  Jose A Morón  4 ,  Gerald W Zamponi  3 ,  Tuan Trang  8  9
Affiliations
  • 1. Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.
  • 2. Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
  • 3. Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
  • 4. Department of Anesthesiology, Washington University School of Medicine, Washington University Pain Center, St. Louis, MO, USA.
  • 5. Department of Anesthesiology & Perioperative Medicine, University of California Los Angeles, Los Angeles, CA, USA.
  • 6. Department of Chemistry, University of Calgary, Calgary, AB, Canada.
  • 7. Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
  • 8. Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada. [email protected].
  • 9. Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada. [email protected].
  • # Contributed equally.
PMID: 39048565 DOI: 10.1038/s41467-024-50657-7
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.

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