Possible involvement of increase in spinal fibronectin following peripheral nerve injury in upregulation of microglial P2X4, a key molecule for mechanical allodynia.
We have recently demonstrated that the P2X4 receptor, an ATP-gated cation channel, in spinal microglia is a key molecule that mediates the mechanical allodynia induced by peripheral nerve injury. Although microglial P2X4 receptor expression is increased after peripheral nerve injury, the molecular mechanism(s) underlying its upregulation remains largely unknown. Fibronectin is a member of the extracellular matrix molecules and is actively produced in response to injury and diseases in the CNS. Here, we describe the influence of fibronectin on P2X4 receptor expression in microglia and the upregulation of fibronectin after peripheral nerve injury. Microglia that were cultured on fibronectin-coated dishes showed a marked increase in P2X4 receptor expression, both at the mRNA and protein levels, as compared to those cultured on control dishes. Fibronectin also enhanced the microglial Ca2+ responses mediated by P2X4 receptors. Moreover, Western blot examination of the spinal cord from a rat with spinal nerve injury indicated that fibronectin was upregulated on the ipsilateral side. Interestingly, intrathecal injection of ATP-stimulated microglia to the rat lumber spinal cord revealed that microglia cultured on fibronectin-coated dishes was more effective in the induction of allodynia than microglia cultured on control dishes. Taken together, our results suggest that spinal fibronectin is elevated after the peripheral nerve injury and it may be involved in the upregulation of the P2X4 receptor in microglia, which leads to the induction of neuropathic pain.
Nasu-Tada
Kaoru
K
Division of Pharmacology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
Koizumi
Schuichi
S
Tsuda
Makoto
M
Kunifusa
Emiko
E
Inoue
Kazuhide
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D016380:Brain Tissue Transplantation; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005353:Fibronectins / Q000378:metabolism* / Q000494:pharmacology; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D009437:Neuralgia / Q000378:metabolism / Q000503:physiopathology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000378:metabolism / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058848:Receptors, Purinergic P2X4; D013116:Spinal Cord / Q000378:metabolism* / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D005353:Fibronectins; C548228:P2rx4 protein, rat; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D058848:Receptors, Purinergic P2X4; D000255:Adenosine Triphosphate; D002118:Calcium