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Nat Med. 2017 Mar;23(3):355-360. doi: 10.1038/nm.4281. Epub 2017 Jan 30.

Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents.

Author information

1
Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.
2
Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
3
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
4
Department of Psychology, University of Calgary, Calgary, Alberta, Canada.
5
Department of Anesthesiology and Perioperative Care, University of California Irvine, Irvine, California, USA.
6
Department of Psychiatry and Neuroscience, Institut Universitaire en santé mentale de Québec, Université Laval, Ville de Québec, Québec, Canada.

Abstract

Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide (10panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia.

PMID:
28134928
DOI:
10.1038/nm.4281
[Indexed for MEDLINE]
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