title: Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents.
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.
authors.affiliation: Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.|Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Burma
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert P
authors.identifier: http://orcid.org/0000-0002-3287-6803
authors.initials: RP
authors.lastname: Bonin
authors.affiliation: Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.|Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Heather
authors.initials: H
authors.lastname: Leduc-Pessah
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Corey
authors.initials: C
authors.lastname: Baimel
authors.affiliation: Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.|Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Zoe F
authors.initials: ZF
authors.lastname: Cairncross
authors.affiliation: Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.|Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Mousseau
authors.affiliation: Department of Psychology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jhenkruthi Vijaya
authors.initials: JV
authors.lastname: Shankara
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Stemkowski
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Dinara
authors.initials: D
authors.lastname: Baimoukhametova
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jaideep S
authors.initials: JS
authors.lastname: Bains
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Psychology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Michael C
authors.identifier: http://orcid.org/0000-0001-5178-4683
authors.initials: MC
authors.lastname: Antle
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California Irvine, Irvine, California, USA.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cahill
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Borgland
authors.affiliation: Department of Psychiatry and Neuroscience, Institut Universitaire en santé mentale de Québec, Université Laval, Ville de Québec, Québec, Canada.
authors.forename: Yves
authors.identifier: http://orcid.org/0000-0002-5779-9330
authors.initials: Y
authors.lastname: De Koninck
authors.affiliation: Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.|Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Tuan
authors.initials: T
authors.lastname: Trang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001081:Apyrase / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western; D018929:Cell Culture Techniques; D018920:Coculture Techniques; D017630:Connexins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015767:Mefloquine / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000009:adverse effects; D009294:Narcotics / Q000009:adverse effects*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D059225:Nociception / Q000187:drug effects; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000235:genetics* / Q000378:metabolism
chemical_list: D017630:Connexins; D009292:Narcotic Antagonists; D009294:Narcotics; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; C479936:pannexin 1, rat; D009270:Naloxone; D009020:Morphine; D000255:Adenosine Triphosphate; D001081:Apyrase; D011339:Probenecid; D015767:Mefloquine