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

Proc Natl Acad Sci U S A. 2009 May 12;106(19):8032-7. doi: 10.1073/pnas.0810420106. Epub 2009 Apr 20.


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-gamma (IFN-gammaR) 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-gammaR 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-gamma-stimulated spinal microglia show up-regulation of Lyn tyrosine kinase and purinergic P2X(4) receptor, crucial events for neuropathic pain, and genetic approaches provide evidence linking these events to IFN-gammaR-dependent microglial and behavioral alterations. These results suggest that IFN-gammaR is a key element in the molecular machinery through which resting spinal microglia transform into an activated state that drives neuropathic pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Interferon gamma Receptor
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microglia / metabolism*
  • Pain / metabolism*
  • Rats
  • Rats, Wistar
  • Receptors, Interferon / metabolism*
  • Receptors, Purinergic P2 / metabolism
  • Receptors, Purinergic P2X4
  • Signal Transduction
  • Spine / metabolism*
  • Up-Regulation
  • src-Family Kinases / metabolism


  • Cytokines
  • P2rx4 protein, mouse
  • Receptors, Interferon
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2X4
  • lyn protein-tyrosine kinase
  • src-Family Kinases