Neuropathic pain is a highly debilitating chronic pain that occurs after nerve injury and is resistant to currently available treatments. We reported that activated microglia overexpressed P2X4 receptors after nerve injury which release brain-derived neurotrophic factor (BDNF) evoking a collapse of their transmembrane anion gradient and the subsequent neuronal hyper-excitability (Nature, 2003 & 2005). Recently, we found that a single intrathecal administration of IFN-γ to normal animals produces a long-lasting tactile allodynic behavior and activation of microglia in the spinal cord. The expression of IFN-γ receptor mRNA in the spinal cord is localized predominantly in microglia. IFN-γ evoked P2X4 up-regulation through Lin-kinase activation in microglia. Furthermore, IFN-γ receptor-deficient mice (ifngr-/-) exhibited a striking reduction in nerve injury-induced tactile allodynia and activation of microglia. We also found that CCL2, ligands for CCR2, increased P2X4R expression in microglial surface fraction. These findings suggest that IFN-γ signaling through IFN-γR plays as a crucial trigger of microglia activation after nerve injury and the subsequent tactile allodynia through P2X4 stimulation, and that CCR2 signaling may increase the P2X4R expression on the surface membrane of microglia. Microglia become activated by multiple types of damage in the nervous system, and play essential roles in neuronal pathologies. However, how microglia transform into reactive phenotypes is poorly understood. Then, we identified the transcription factor interferon-regulatory factor 8 (IRF8) as a critical regulator of reactive microglia. IRF8 expression was markedly upregulated in microglia, but not in neurons or astrocytes, after nerve injury. IRF8 overexpression in cultured microglia promoted the transcription of genes associated with reactive states; conversely, IRF8 deficiency prevented these gene expressions in the spinal cord following PNI. Furthermore, IRF8-deficient mice were resistant to neuropathic pain, and transferring IRF8-overexpressing microglia spinally to normal mice produced pain. Therefore, IRF8 may activate a program of gene expression that transforms microglia into a reactive phenotype.