|Budget Amount *help
¥4,100,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥600,000)
Fiscal Year 2007: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Persistent pain hypersensitivity such as hyperalgesia and allodynia is produced by peripheral tissue injury, inflammation or nerve injury. Interthecal application of poteasome inhibitors in rats with chronic constriction sciatic nerve injury attenuated hyperalgesia and allodynia, suggesting that the selective protein degradation via ubiquitin-proteasome system may play a role in synaptic modifications for persistent pain. We previously demonstrated that the activation of NMDA subtype of glutamate receptor and subsequent production of nitric oxide (NO) by neuronal NO synthase (nNOS) in the spinal cord are involved in the maintenance of neuropathic pain. Here, we studied the expression level of ubiquitin-proteasome system related molecules, Fbx2, CHIP, Mdm2, UCHL1 and Usp14, in mouse spinal cord during neuropathic pain and inflammatory pain. Ubiquitin ligases, Fbx2, CHIP and Mdm2, ubiquitinate NR1 subunit of NMDA glutamate receptor, nNOS and post-synaptic density 95 (PSD95), respectively. UCHL1 and Usp14 are de-ubiquitinating enzymes. The expression of Mdm2 mRNA was increased in the spinal cord 7 days after nerve injury produced by L5 spinal nerve transection. The degradation of PSD95 via Mdm2 may affect the interaction between nNOS and NMDA glutamate receptor and the surface expression and internalization of AMPA glutamate receptor in neuropathic pain. On the other hand, the expression of Fbx2 mRNA was increased in the spinal cord 1 day after inflammatory pain induced by intraplantar injection of complete Freund's adjuvant. Fbx2 ubiquitinates NR1 in the retrotranslocated ectodomain, and the degradation of NR1 may involve in the inflammatory pain. These results suggest that both neuropathic pain and inflammatory pain may be maintained by dynamic change of synaptic composition such as glutamate receptors and nNOS through the ubiquitin-proteasome system.