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BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain

Nature volume 438, pages 1017–1021 (2005)Cite this article

Abstract

Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord1,2,3. Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury4. Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential (Eanion) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (γ-amino butyric acid), as has been shown to occur after peripheral nerve injury5. Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in Eanion. Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the Eanion shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and Eanion. Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia–neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.

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Figure 1: Spinal delivery of ATP-stimulated microglia to rats evokes allodynia and a depolarizing shift in E anion in spinal LI neurons.
Figure 2: Enhanced BDNF in the dorsal horn elicits nociceptive hypersensitivity and a depolarizing shift in E anion in spinal LI neurons.
Figure 3: Functional inhibition of BDNF–TrkB signalling reverses allodynia and the depolarizing shift in E anion in spinal LI neurons in rats with PNI.
Figure 4: Microglia-derived BDNF triggers both allodynia and the depolarizing shift in E anion in LI neurons.

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Acknowledgements

We thank F. Nault for technical assistance; J. Zhang for conducting OX42 immunostaining; and P. De Koninck, M. Cordero-Erausquin, F. Keller and C. Labrakakis for discussions on the manuscript. This work was supported by Canadian Institutes of Health Research (CIHR) grants (to Y.D.K. and to M.W.S.), Brain Repair Program of Neuroscience Canada and its partner the Ontario Neurotrauma Foundation through the BRP. J.A.M.C. was the recipient of a doctoral award from the CIHR; Y.D.K. is a Senior Scholar of the Fonds de la recherche en santé du Québec (FRSQ); S.B. was the recipient of a fellowship from a Strategic Training Program Grant from the CIHR.

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  1. Jeffrey A. M. Coull and Simon Beggs: *These authors contributed equally to this work

Authors and Affiliations

  1. Division de Neurobiologie Cellulaire, Centre de Recherche Université Laval Robert-Giffard, Québec, G1J 2G3, Québec, Canada

    Jeffrey A. M. Coull, Dominic Boudreau, Dominick Boivin & Yves De Koninck

  2. Department of Pharmacology & Therapeutics, McGill University, Montréal, H3G 1Y6, Québec, Canada

    Jeffrey A. M. Coull & Yves De Koninck

  3. Therapeutics, McGill University, Montréal

    Jeffrey A. M. Coull & Yves De Koninck

  4. Programme in Brain and Behaviour, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Simon Beggs, Makoto Tsuda & Michael W. Salter

  5. Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, 812-8582, Higashi, Fukuoka, Japan

    Makoto Tsuda & Kazuhide Inoue

  6. Division de Neurobiologie Systémique, Centre de recherche Université Laval Robert-Giffard, Québec, G1J 2G3, Québec, Canada

    Claude Gravel

  7. Département de Psychiatrie, Université Laval, Québec, G1K 7P4, Québec, Canada

    Claude Gravel & Yves De Koninck

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Correspondence to Michael W. Salter or Yves De Koninck.

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Coull, J., Beggs, S., Boudreau, D. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005). https://doi.org/10.1038/nature04223

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