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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 19; p. 8032
• Main Authors: Tsuda, Makoto, Masuda, Takahiro, Kitano, Junko, Shimoyama, Hiroshi, Tozaki-Saitoh, Hidetoshi, Inoue, Kazuhide
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 12.05.2009
• Subjects: Cells; Cytokines; Genetics; Neurons; Pain
• ISSN: 0027-8424; 1091-6490

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