Fibronectin/integrin system is involved in P2X4 receptor upregulation in the spinal cord and neuropathic pain after nerve injury

Tsuda Makoto, Emika Toyomitsu, Takayuki Komatsu, Takahiro Masuda, Emiko Kunifusa, Kaoru Nasu-Tada, Schuichi Koizumi, Kimiko Yamamoto, Joji Ando, Kazuhide Inoue

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

We have previously shown that activation of the ATP-gated ion channel subtype P2X4 receptors (P2X4Rs) in the spinal cord, the expression of which is upregulated in microglia after nerve injury, is necessary for producing neuropathic pain. The upregulation of P2X4Rs in microglia is, therefore, a key process in neuropathic pain, but the mechanism remains unknown. Here, we find a fibronectin/integrin-dependent mechanism in the upregulation of P2X4Rs. Microglia cultured on dishes coated with fibronectin, an extracellular matrix molecule, expressed a higher level of P2X4R protein when compared with those cultured on control dishes. The increase was suppressed by echistatin, a peptide that selectively blocks β1 and β3-containing integrins, and with a function-blocking antibody of β1 integrin. In in vivo studies, the upregulation of P2X4Rs in the spinal cord after spinal nerve injury was significantly suppressed by intrathecal administration of echistatin. Tactile allodynia in response to nerve injury and intrathecal administration of ATP- and fibronectin-stimulated microglia was inhibited by echistatin. Furthermore, intrathecal administration of fibronectin in normal rats increased the level of P2X4R protein in the spinal cord and produced tactile allodynia. Moreover, the fibronectin-induced allodynia was not observed in mice lacking P2X4R. Taken together with the results of our previous study showing an increase in the spinal fibronectin level after nerve injury, the present results suggest that the fibronectin/integrin system participates in the upregulation of P2X4R expression after nerve injury and subsequent neuropathic pain.

Original languageEnglish
Pages (from-to)579-585
Number of pages7
JournalGLIA
Volume56
Issue number5
DOIs
Publication statusPublished - Apr 1 2008

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Purinergic P2X4 Receptors
Neuralgia
Fibronectins
Integrins
Spinal Cord
Up-Regulation
Microglia
Wounds and Injuries
Hyperalgesia
Adenosine Triphosphate
Spinal Injuries
Spinal Nerves
Blocking Antibodies
Ion Channels
Extracellular Matrix
Proteins
Peptides

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Fibronectin/integrin system is involved in P2X4 receptor upregulation in the spinal cord and neuropathic pain after nerve injury. / Makoto, Tsuda; Toyomitsu, Emika; Komatsu, Takayuki; Masuda, Takahiro; Kunifusa, Emiko; Nasu-Tada, Kaoru; Koizumi, Schuichi; Yamamoto, Kimiko; Ando, Joji; Inoue, Kazuhide.

In: GLIA, Vol. 56, No. 5, 01.04.2008, p. 579-585.

Research output: Contribution to journalArticle

Makoto, T, Toyomitsu, E, Komatsu, T, Masuda, T, Kunifusa, E, Nasu-Tada, K, Koizumi, S, Yamamoto, K, Ando, J & Inoue, K 2008, 'Fibronectin/integrin system is involved in P2X4 receptor upregulation in the spinal cord and neuropathic pain after nerve injury', GLIA, vol. 56, no. 5, pp. 579-585. https://doi.org/10.1002/glia.20641
Makoto, Tsuda ; Toyomitsu, Emika ; Komatsu, Takayuki ; Masuda, Takahiro ; Kunifusa, Emiko ; Nasu-Tada, Kaoru ; Koizumi, Schuichi ; Yamamoto, Kimiko ; Ando, Joji ; Inoue, Kazuhide. / Fibronectin/integrin system is involved in P2X4 receptor upregulation in the spinal cord and neuropathic pain after nerve injury. In: GLIA. 2008 ; Vol. 56, No. 5. pp. 579-585.
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