Journal Article

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

Beggs, Simon, Boudreau, Dominic, Tsuda, Makoto, Gravel, Claude, Salter, Michael W., Boivin, Dominick, De Koninck, Yves, Inoue, Kazuhide, Coull, Jeffrey A. M.

2005

Overview

GABA is a pain Neuropathic pain, one of the most debilitating of all pain states, often arises from injury to a peripheral nerve that depends on activation of a specific cell type known as microglia. This prompts the question, how do the microglia signal to spinal pain neurons? Coull et al . have now identified the biophysical mechanism by which microglia, activated by ATP, cause hyperexcitability of spinal neurons. The microglia release brain-derived neurotrophic factor, which alters chloride ion distribution across the plasma membrane of neurons in lamina I of the spinal cord. This results in the neurotransmitter, GABA, activating (rather than inhibiting) these cells that form part of a major pathway that signals pain. A collection of recent reprints on neuropathic pain, taken from Nature Publishing Group journals is, now available online via tinyurl.com/dzw86. 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 injury 4 . 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 (γ-amino butyric acid), as has been shown to occur after peripheral nerve injury 5 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Adenosine Triphosphate - pharmacology / Amino acids / Animals / Anions - metabolism / ATP / Biological and medical sciences / Brain / Brain-Derived Neurotrophic Factor - genetics / Brain-Derived Neurotrophic Factor - metabolism / Brain-Derived Neurotrophic Factor - pharmacology / Brain-Derived Neurotrophic Factor - secretion / Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes / Humanities and Social Sciences / letter / Male / Medical sciences / Membrane Potentials - drug effects / Microglia - drug effects / Microglia - secretion / multidisciplinary / Nervous system (semeiology, syndromes) / Neurology / Neurons / Neurons - drug effects / Neurons - metabolism / Pain / Pain - physiopathology / Pain management / Posterior Horn Cells - metabolism / Rats / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Spinal Cord - cytology / Spinal cord injuries / Therapy