Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development

Knut Biber, Makoto Tsuda, Hidetoshi Tozaki-Saitoh, Keiko Tsukamoto, Emika Toyomitsu, Takahiro Masuda, Hendrikus Boddeke, Kazuhide Inoue

Research output: Contribution to journalArticlepeer-review

147 Citations (Scopus)


Up-regulation of P2X4 receptors in spinal cord microglia is crucial for tactile allodynia, an untreatable pathological pain reaction occurring after peripheral nerve injury. How nerve injury in the periphery leads to this microglia reaction in the dorsal horn of the spinal cord is not yet understood. It is shown here that CCL21 was rapidly expressed in injured small-sized primary sensory neurons and transported to their central terminals in the dorsal horn. Intrathecal administration of a CCL21-blocking antibody diminished tactile allodynia development in wild-type animals. Mice deficient for CCL21 did not develop any signs of tactile allodynia and failed to up-regulate microglial P2X4 receptor expression. Microglia P2X4 expression was enhanced by CCL21 application in vitro and in vivo. A single intrathecal injection of CCL21 to nerve-injured CCL21-deficient mice induced long-lasting allodynia that was undistinguishable from the wild-type response. This effect of CCL21 injection was strictly dependent on P2X4 receptor function. Since neuronal CCL21 is the earliest yet identified factor in the cascade leading to tactile allodynia, these findings may lead to a preventive therapy in neuropathic pain.

Original languageEnglish
Pages (from-to)1864-1873
Number of pages10
JournalEMBO Journal
Issue number9
Publication statusPublished - May 4 2011

All Science Journal Classification (ASJC) codes

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology


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