IFN-γ receptor signaling mediates spinal microglia activation driving neuropathic pain

Makoto Tsuda, Takahiro Masuda, Junko Kitano, Hiroshi Shimoyama, Hidetoshi Tozaki-Saitoh, Kazuhide Inoue

Research output: Contribution to journalArticlepeer-review

177 Citations (Scopus)

Abstract

Neuropathic pain, a highly debilitating pain condition that commonly occurs after nerve damage, is a reflection of the aberrant excitability of dorsal horn neurons. This pathologically altered neurotransmission requires a communication with spinal microglia activated by nerve injury. However, how normal resting microglia become activated remains unknown. Here we show that in naive animals spinal microglia express a receptor for the cytokine IFN-γ (IFN-γR) in a cell-type-specific manner and that stimulating this receptor converts microglia into activated cells and produces a long-lasting pain hypersensitivity evoked by innocuous stimuli (tactile allodynia, a hallmark symptom of neuropathic pain). Conversely, ablating IFN-γR severely impairs nerve injury-evoked microglia activation and tactile allodynia without affecting microglia in the contralateral dorsal horn or basal pain sensitivity. We also find that IFN-γ-stimulated spinal microglia show up-regulation of Lyn tyrosine kinase and purinergic P2X4 receptor, crucial events for neuropathic pain, and genetic approaches provide evidence linking these events to IFN-γR-dependent microglial and behavioral alterations. These results suggest that IFN-γR is a key element in the molecular machinery through which resting spinal microglia transform into an activated state that drives neuropathic pain.

Original languageEnglish
Pages (from-to)8032-8037
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number19
DOIs
Publication statusPublished - May 12 2009

All Science Journal Classification (ASJC) codes

  • General

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