Fibronectin/integrin system is involved in P2X4 receptor upregulation in the spinal cord and neuropathic pain after nerve injury
✍ Scribed by Makoto Tsuda; Emika Toyomitsu; Takayuki Komatsu; Takahiro Masuda; Emiko Kunifusa; Kaoru Nasu-Tada; Schuichi Koizumi; Kimiko Yamamoto; Joji Ando; Kazuhide Inoue
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 277 KB
- Volume
- 56
- Category
- Article
- ISSN
- 0894-1491
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✦ Synopsis
We have previously shown that activation of the ATP-gated ion channel subtype P2X 4 receptors (P2X 4 Rs) in the spinal cord, the expression of which is upregulated in microglia after nerve injury, is necessary for producing neuropathic pain. The upregulation of P2X 4 Rs 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 P2X 4 Rs. Microglia cultured on dishes coated with fibronectin, an extracellular matrix molecule, expressed a higher level of P2X 4 R protein when compared with those cultured on control dishes. The increase was suppressed by echistatin, a peptide that selectively blocks b 1 and b 3 -containing integrins, and with a function-blocking antibody of b 1 integrin. In in vivo studies, the upregulation of P2X 4 Rs 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 P2X 4 R protein in the spinal cord and produced tactile allodynia. Moreover, the fibronectin-induced allodynia was not observed in mice lacking P2X 4 R. 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 P2X 4 R expression after nerve injury and subsequent neuropathic pain. V