title: Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain.
abstract: One of the most significant advances in pain research is the realization that neurons are not the only cell type involved in the etiology of chronic pain. This realization has caused a radical shift from the previous dogma that neuronal dysfunction alone accounts for pain pathologies to the current framework of thinking that takes into account all cell types within the central nervous system (CNS). This shift in thinking stems from growing evidence that glia can modulate the function and directly shape the cellular architecture of nociceptive networks in the CNS. Microglia, in particular, are increasingly recognized as active principal players that respond to changes in physiological homeostasis by extending their processes toward the site of neural damage, and by releasing specific factors that have profound consequences on neuronal function and that contribute to CNS pathologies caused by disease or injury. A key molecule that modulates microglia activity is ATP, an endogenous ligand of the P2 receptor family. Microglia expresses several P2 receptor subtypes, and of these the P2X4 receptor subtype has emerged as a core microglia-neuron signaling pathway: activation of this receptor drives the release of brain-derived neurotrophic factor (BDNF), a cellular substrate that causes disinhibition of pain-transmitting spinal lamina I neurons. Converging evidence points to BDNF from spinal microglia as being a critical microglia-neuron signaling molecule that gates aberrant nociceptive processing in the spinal cord. The present review highlights recent advances in our understanding of P2X4 receptor-mediated signaling and regulation of BDNF in microglia, as well as the implications for microglia-neuron interactions in the pathobiology of neuropathic pain.
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Department of Physiology, University of Toronto and University of Toronto Centre for Study of Pain, Toronto, Ontario, Canada.
authors.forename: Tuan
authors.initials: T
authors.lastname: Trang
authors.forename: Simon
authors.initials: S
authors.lastname: Beggs
authors.forename: Michael W
authors.initials: MW
authors.lastname: Salter
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002490:Central Nervous System / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D017628:Microglia / Q000378:metabolism*; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058469:Receptors, Purinergic P2X / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D058469:Receptors, Purinergic P2X