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Pannexin-1 channel inhibition alleviates opioid withdrawal in rodents by modulating locus coeruleus to spinal cord circuitry.
- Source :
-
Nature communications [Nat Commun] 2024 Jul 24; Vol. 15 (1), pp. 6264. Date of Electronic Publication: 2024 Jul 24. - Publication Year :
- 2024
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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 (LC <superscript>spinal</superscript> ) are hyperexcitable during morphine withdrawal, elevating cerebrospinal fluid (CSF) levels of norepinephrine. Pharmacological and chemogenetic silencing of LC <superscript>spinal</superscript> 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.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Mice
Male
Rats
Morphine pharmacology
Microglia drug effects
Microglia metabolism
Analgesics, Opioid pharmacology
Norepinephrine metabolism
Neurons metabolism
Neurons drug effects
Mice, Inbred C57BL
Rats, Sprague-Dawley
Tyrosine 3-Monooxygenase metabolism
Mice, Knockout
Locus Coeruleus metabolism
Locus Coeruleus drug effects
Connexins metabolism
Connexins genetics
Connexins antagonists & inhibitors
Nerve Tissue Proteins metabolism
Nerve Tissue Proteins genetics
Substance Withdrawal Syndrome metabolism
Substance Withdrawal Syndrome drug therapy
Spinal Cord metabolism
Spinal Cord drug effects
Probenecid pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 39048565
- Full Text :
- https://doi.org/10.1038/s41467-024-50657-7