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

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

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

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
Volume30
Issue number9
DOIs
Publication statusPublished - May 4 2011

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Purinergic P2X4 Receptors
Hyperalgesia
Microglia
Neuralgia
Up-Regulation
Blocking Antibodies
Neurons
Animals
Spinal Injections
Peripheral Nerve Injuries
Wild Animals
Sensory Receptor Cells
Spinal Cord
Pain
Injections
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. / Biber, Knut; Makoto, Tsuda; Saitoh, Hidetoshi; Tsukamoto, Keiko; Toyomitsu, Emika; Masuda, Takahiro; Boddeke, Hendrikus; Inoue, Kazuhide.

In: EMBO Journal, Vol. 30, No. 9, 04.05.2011, p. 1864-1873.

Research output: Contribution to journalArticle

Biber, Knut ; Makoto, Tsuda ; Saitoh, Hidetoshi ; Tsukamoto, Keiko ; Toyomitsu, Emika ; Masuda, Takahiro ; Boddeke, Hendrikus ; Inoue, Kazuhide. / Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. In: EMBO Journal. 2011 ; Vol. 30, No. 9. pp. 1864-1873.
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