BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain.
Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord. Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury. 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 (gamma-amino butyric acid), as has been shown to occur after peripheral nerve injury. 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.
Coull
Jeffrey A M
JA
Division de Neurobiologie Cellulaire, Centre de Recherche Université Laval Robert-Giffard, Québec, Québec G1J 2G3, Canada.
Beggs
Simon
S
Boudreau
Dominic
D
Boivin
Dominick
D
Tsuda
Makoto
M
Inoue
Kazuhide
K
Gravel
Claude
C
Salter
Michael W
MW
De Koninck
Yves
Y
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000838:Anions / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000503:physiopathology*; D020671:Posterior Horn Cells / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology
D000838:Anions; D019208:Brain-Derived Neurotrophic Factor; D034741:RNA, Small Interfering; D000255:Adenosine Triphosphate