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

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-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.

• Authors: Makoto Tsuda, Takahiro Masuda, Junko Kitano, Hiroshi Shimoyama, Hidetoshi Tozaki-Saitoh, Kazuhide Inoue
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 19 Pg. 8032-7 (May 12 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19380717 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Cytokines (metabolism)
• 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)