Abstract

A large and rapidly increasing body of evidence indicates that microglia-to-neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, we found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research.

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Acknowledgements

This work was supported by the Canadian Institutes of Health Research (MOP-123307; M.W.S. and J.S.M.), the Canada Research Chair Program (M.W.S. and J.S.M.), the Louise and Alan Edwards Foundation (J.S.M.), the Anne and Max Tanenbaum Chair Program (M.W.S.), and the US National Institutes of Health (R01-DE17794; R.-R.J.).

Author information

Author notes

    • Robert E Sorge
    •  & Josiane C S Mapplebeck

    These authors contributed equally to this work.

Affiliations

  1. Department of Psychology, McGill University, Montreal, Quebec, Canada.

    • Robert E Sorge
    • , Josiane C S Mapplebeck
    • , Sarah Rosen
    • , Loren J Martin
    • , Jean-Sebastien Austin
    • , Susana G Sotocinal
    • , Di Chen
    •  & Jeffrey S Mogil
  2. Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Robert E Sorge
  3. Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada.

    • Josiane C S Mapplebeck
    • , Simon Beggs
    • , Jessica K Alexander
    • , YuShan Tu
    •  & Michael W Salter
  4. Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

    • Josiane C S Mapplebeck
    • , Simon Beggs
    • , Jessica K Alexander
    •  & Michael W Salter
  5. University of Toronto Centre for the Study of Pain, Toronto, Ontario, Canada.

    • Josiane C S Mapplebeck
    • , Simon Beggs
    • , Jessica K Alexander
    •  & Michael W Salter
  6. Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA.

    • Sarah Taves
    •  & Ru-Rong Ji
  7. Faculty of Dentistry, McGill University, Montreal, Quebec, Canada.

    • Mu Yang
    • , Xiang Qun Shi
    • , Hao Huang
    •  & Ji Zhang
  8. Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.

    • Nicolas J Pillon
    • , Philip J Bilan
    •  & Amira Klip
  9. Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.

    • Ji Zhang
    •  & Jeffrey S Mogil

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Contributions

R.E.S., S.B., R.-R.J., M.W.S. and J.S.M. conceived the study. R.E.S. designed most of the experiments, and J.C.S.M. and J.Z. designed certain experiments. R.E.S., J.C.S.M., S.R., S.T., S.B., J.K.A., L.J.M., J.-S.A., S.G.S., D.C., M.Y., X.Q.S., H.H., N.J.P., P.J.B., Y.T. and A.K. collected and analyzed data. R.E.S., J.C.S.M., S.B., M.W.S. and J.S.M. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Michael W Salter or Jeffrey S Mogil.

Integrated supplementary information

Supplementary figures

  1. 1.

    Dose-dependent reversal of SNI-induced allodynia by intrathecal glial inhibitors in male but not female mice.

  2. 2.

    Reversal of complete Freund’s adjuvant (CFA)‑induced mechanical allodynia by intrathecal glial inhibitors minocycline (MCL), fluorocitrate (FC) and propentofylline (PPF) in male but not female mice.

  3. 3.

    Repeated systemic (i.p.) injections of minocycline (MCL) reverse SNI- and CFA‑induced mechanical allodynia in male but not female mice.

  4. 4.

    Testosterone‑dependence of the efficacy of minocycline in reversing CFA-induced allodynia.

  5. 5.

    Spinal microgliosis 7 days after SNI in male (left) and female (right) mice.

  6. 6.

    Microglial depletion by intrathecal Mac-1-saporin treatment in male and female mice.

  7. 7.

    SNI upregulates expression of the Itgam (CD11b), Emr1 (F4/80; a surface marker for microglia), Irf5, and Irf8 genes (see below) in the dorsal horn of the spinal cord equally in both sexes, but only upregulates the P2rx4 gene (P2X4R) in male mice.

  8. 8.

    Nerve injury-induced microglia responses are present in microglial-specific Bdnf mutant mice of both sexes.

  9. 9.

    Reversal of developed SNI‑induced mechanical allodynia in male Bdnf−/− mice.

  10. 10.

    Quantitative sex differences in baseline mechanical sensitivity (a) and SNI- and CFA-induced mechanical allodynia (b–e) in various experiments.

  11. 11.

    Female nude mice “switch” to a microglial-dependent system in the mediation of CFA allodynia.

  12. 12.

    Female Rag1−/− mice “switch” to a microglial-dependent system in the mediation of SNI and CFA allodynia.

  13. 13.

    Adoptive transfer of splenocytes into female Rag1−/− mice reinstates their use of the female glial-independent pathway.

  14. 14.

    Female mice have a larger pool of T-cells in the blood than do male mice.

  15. 15.

    Higher expression of T-cell markers in the lumbar spinal cord dorsal horns of female versus male CD-1 mice 7 days after SNI.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–15

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DOI

https://doi.org/10.1038/nn.4053

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