Abstract
Neuropathic pain, a highly debilitating chronic pain following nerve damage, is a reflection of the aberrant functioning of a pathologically altered nervous system. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. While the dominant theme in research on neuropathic pain has been to understand the roles of neurons in the peripheral nervous system and the dorsal horn, there is a rapidly growing body of evidence indicating that glia, especially microglia, in the spinal cord are activated following nerve injury. Here we will present recent evidence that activated spinal microglia are the cause and key cellular intermediaries in the pathogenesis of neuropathic pain. In activated microglia, P2X4 receptor (P2X4Rs), a ligand-gated cation channel activated by ATP, is a required molecular mediator. P2X4Rs in the spinal cord are upregulated exclusively in activated microglia after nerve injury. Blocking P2X4Rs leads to a reversal of neuropathic pain. We will also show recent findings that fibronectin, an extracellular matrix protein, causes an increase in the expression of P2X4Rs in microglia and that P2X4-stimulated microglia cause a release of brain-derived neurotrophic factor (BDNF) that mediates signaling between activated microglia and pain-transmission dorsal horn neurons. Understanding of how P2X4Rs are expressed and activated in spinal microglia following nerve injury may lead to new strategies that may aid in the management of neuropathic pain. [J Physiol Sci. 2007;57 Suppl:S9]
