Lyn tyrosine kinase is required for P2X4 receptor upregulation and neuropathic pain after peripheral nerve injury

Makoto Tsuda, Hidetoshi Tozaki-Saitoh, Takahiro Masuda, Emika Toyomitsu, Tohru Tezuka, Tadashi Yamamoto, Kazuhide Inoue

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Neuropathic pain, a debilitating chronic pain following nerve damage, is a reflection of the aberrant functioning of a pathologically altered nervous system. One hallmark is abnormal pain hypersensitivity to innocuous stimuli (tactile allodynia), for which effective therapy is lacking, and the underlying mechanisms of which remain to be determined. Here we show that Lyn, a member of the Src family kinases (SFKs), plays an important role in the pathogenesis of neuropathic pain. Nerve injury, but not peripheral inflammation, increased immunoreactivity for active SFKs that were autophosphorylated in the kinase domain (phospho-SFK-IR) in spinal microglia. In spinally derived microglial cells, we identified Lyn as the predominant SFK among the five members (Src, Fyn, Yes, Lck, and Lyn) known to be expressed in the CNS. Lyn expression in the spinal cord was highly restricted to microglia, and its level was increased after nerve injury. We found that mice lacking lyn (lyn-/-) exhibit a striking reduction in the levels of phospho-SFK-IR and tactile allodynia after nerve injury, without any change in basal mechanical sensitivity or inflammatory pain. Importantly, lyn-/- mice displayed impaired upregulation of the ionotropic ATP receptor subtype P2X4 receptors (P2X4R) in the spinal cord after nerve injury, which is crucial for tactile allodynia. Microglial cells from lyn-/- mice showed a deficit in their ability to increase P2X4R expression in response to fibronectin, a factor implicated as a microglial P2X4R upregulator in allodynia. Together, our findings suggest that Lyn may be a critical kinase mediating nerve injury-induced P2X4R upregulation and neuropathic pain.

Original languageEnglish
Pages (from-to)50-58
Number of pages9
JournalGLIA
Volume56
Issue number1
DOIs
Publication statusPublished - Jan 1 2008

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience

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