1. Division de Neurobiologie Cellulaire, Centre de Recherche Université Laval Robert-Giffard, Québec, Québec G1J 2G3, Canada
2. Department of Pharmacology & Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada
3. Programme in Brain and Behaviour, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
4. Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka 812-8582, Japan
5. Division de Neurobiologie Systémique, Centre de recherche Université Laval Robert-Giffard, Québec, Québec G1J 2G3, Canada
6. Département de Psychiatrie, Université Laval, Québec, Québec G1K 7P4, Canada
7. *These authors contributed equally to this work

Correspondence to: Michael W. Salter³Yves De Koninck^1,2,6 Correspondence and requests for materials should be addressed to Y.D.K. (Email: Yves.DeKoninck@crulrg.ulaval.ca) or M.W.S. (Email: mike.salter@utoronto.ca).

Abstract

Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord^{1, 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 (E_anion) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (-amino butyric acid), as has been shown to occur after peripheral nerve injury⁵. Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E_anion. Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E_anion 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 E_anion. 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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