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

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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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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