Premium
Fibronectin/integrin system is involved in P2X 4 receptor upregulation in the spinal cord and neuropathic pain after nerve injury
Author(s) -
Tsuda Makoto,
Toyomitsu Emika,
Komatsu Takayuki,
Masuda Takahiro,
Kunifusa Emiko,
NasuTada Kaoru,
Koizumi Schuichi,
Yamamoto Kimiko,
Ando Joji,
Inoue Kazuhide
Publication year - 2008
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20641
Subject(s) - neuropathic pain , downregulation and upregulation , fibronectin , spinal cord injury , spinal cord , nerve injury , biology , neuroscience , integrin , receptor , medicine , microbiology and biotechnology , gene , extracellular matrix , biochemistry
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 β 1 and β 3 ‐containing integrins, and with a function‐blocking antibody of β 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. © 2008 Wiley‐Liss, Inc.