• An Erratum to this article was published on 06 June 2017

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 opiates1,2,3,4. 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 ATP5,6. 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.

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Change history

  • Corrected online 15 February 2017

    In the version of this article initially published online, Yves De Koninck’s name was misspelled in the author list. The original version listed Yves DeKoninck. The error has been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

We thank D. Littman and W.-B. Gan (both at New York University School of Medicine) for generously providing breeding pairs for the Cx3cr1-CreERT2 mouse colony, R. Thompson (University of Calgary) for providing the Panx1flx/flx mice, and F. Visser for mouse genotyping. BV-2 microglial-like cells were provided by M. Tsuda (Kyushu University) and K. Biber (University of Groningen). We also thank K. Jhamandas and B. Zochodne for comments on the manuscript and the RUN CORE Facility for access to the Nikon C1S1 confocal and A1R multiphoton microscopes. This work was supported by grants from the Vi Riddell Program for Pediatric Pain, Natural Sciences and Engineering Research Council of Canada (RGPIN418299) and the Rita Allen Foundation and American Pain Society to T.T. Canadian Institutes of Health Research grants were also awarded to T.T. (MOP133523), Y.D.K. (MOP12942) and G.W.Z. (FDN143336). N.E.B. is supported by a Hotchkiss Brain Institute Doctoral Scholarship and a Queen Elizabeth II Scholarship. R.P.B., G.W.Z. and Y.D.K. hold Canada Research Chairs.

Author information

Affiliations

  1. Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.

    • Nicole E Burma
    • , Heather Leduc-Pessah
    • , Zoe F Cairncross
    • , Michael Mousseau
    •  & Tuan Trang
  2. Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

    • Nicole E Burma
    • , Heather Leduc-Pessah
    • , Corey Baimel
    • , Zoe F Cairncross
    • , Michael Mousseau
    • , Patrick L Stemkowski
    • , Dinara Baimoukhametova
    • , Jaideep S Bains
    • , Michael C Antle
    • , Gerald W Zamponi
    • , Stephanie L Borgland
    •  & Tuan Trang
  3. Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.

    • Robert P Bonin
  4. Department of Psychology, University of Calgary, Calgary, Alberta, Canada.

    • Jhenkruthi Vijaya Shankara
    •  & Michael C Antle
  5. Department of Anesthesiology and Perioperative Care, University of California Irvine, Irvine, California, USA.

    • Catherine M Cahill
  6. Department of Psychiatry and Neuroscience, Institut Universitaire en santé mentale de Québec, Université Laval, Ville de Québec, Québec, Canada.

    • Yves De Koninck

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Contributions

N.E.B. and T.T. conceived and designed the project. N.E.B., R.P.B., H.L.-P., C.B., Z.F.C., M.M., J.V.S., P.L.S., D.B. and C.M.C. performed the experiments. T.T., Y.D.K., S.L.B., M.C.A., G.W.Z. and J.S.B. supervised the experiments. N.E.B., R.P.B., H.L.-P., M.C.A. and C.M.C. analyzed the data. N.E.B. and T.T. wrote the manuscript. All authors read and approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tuan Trang.

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https://doi.org/10.1038/nm.4281

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