Analysis for the maintenance of neuropathic pain regulated by protein degradation.

分析蛋白质降解调节的神经性疼痛的维持。

• 批准号: 18613022
• 负责人: ASHITAKA Emiko
• 金额: $ 2.62万
• 依托单位: Kansai Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18613022/
• 关键词: ubiquitin; proteasome; glutamate; NMDA receptor; neuronal nitric oxide synthase; inflammatory pain; neuropathic pain

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.

外周组织损伤、炎症或神经损伤可产生持续性疼痛超敏反应，如痛觉过敏和异常痛觉。慢性收缩性坐骨神经损伤大鼠鞘间应用蛋白酶体抑制剂可减轻痛觉过敏和异位性痛，提示通过泛素-蛋白酶体系统的选择性蛋白质降解可能在持续疼痛的突触修饰中起作用。我们之前已经证明，脊髓中谷氨酸受体NMDA亚型的激活和神经元NO合成酶（nNOS）随后产生一氧化氮（NO）参与了神经性疼痛的维持。我们研究了泛素-蛋白酶体系统相关分子Fbx2、CHIP、Mdm2、UCHL1和Usp14在小鼠脊髓神经性疼痛和炎性疼痛中的表达水平。泛素连接酶Fbx2、CHIP和Mdm2分别是NMDA谷氨酸受体的泛素化NR1亚基、nNOS和突触后密度95 （PSD95）。UCHL1和Usp14是去泛素化酶。L5脊髓神经横断损伤后7天脊髓内Mdm2 mRNA表达升高。通过Mdm2降解PSD95可能影响神经性疼痛中nNOS与NMDA谷氨酸受体的相互作用以及AMPA谷氨酸受体的表面表达和内化。另一方面，足底注射完全弗氏佐剂引起炎症性疼痛后1天脊髓中Fbx2 mRNA表达升高。Fbx2泛素化NR1在逆转录外域，NR1的降解可能参与炎症性疼痛。这些结果提示神经性疼痛和炎性疼痛都可能通过泛素-蛋白酶体系统通过谷氨酸受体和nNOS等突触组成的动态变化来维持。

项目成果

Ornithine transport via cationic amino acid transporter-1 is involved in ornithine cytotoxicity in retinal pigment epithelial cells.

• DOI: 10.1167/iovs.06-0398
• 发表时间: 2007
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: S. Kaneko;A. Ando;E. Okuda‐Ashitaka;Masahide Maeda;K. Furuta*;Masaaki Suzuki;M. Matsumura;S. Ito

Nitric oxide (NO) serves as a retrograde messenger to activate neuronal NO synthase in the spinal cord via NMDA receptors

• DOI: 10.1016/j.niox.2007.04.004
• 发表时间: 2007-08-01
• 期刊: NITRIC OXIDE-BIOLOGY AND CHEMISTRY
• 影响因子: 3.9
• 作者: Xu, Li;Mabuchi, Tamaki;Ito, Seiji
• 通讯作者: Ito, Seiji

The opioid peptide nociceptin/orphanin FQ mediates prostaglandin E2‐induced allodynia, tactile pain associated with nerve injury

• DOI: 10.1111/j.1460-9568.2006.04623.x
• 发表时间: 2006-02
• 期刊: European Journal of Neuroscience
• 影响因子: 3.4
• 作者: E. Okuda‐Ashitaka;T. Minami;S. Matsumura;H. Takeshima;R. Reinscheid;O. Civelli;S. Ito

Cell Apoptosisi:Regulation and Environmental Factors;Prevention of apoptosis by down-regulation of apoptosis related gene expression obtained by nipradilol via nitoric oxide donative action

细胞凋亡：调节和环境因素；尼普地洛通过一氧化氮供体作用下调凋亡相关基因表达来预防细胞凋亡

• 发表时间: 2007
• 作者: Ando;A.
• 通讯作者: A.

慢性疼痛;脊髄後角におけるNMDA受容体リン酸化と神経因性疼痛

慢性疼痛；NMDA 受体磷酸化和脊髓背角神经性疼痛

• 发表时间: 2007
• 作者: Ando;A.;南 敏明;芦高 恵美子
• 通讯作者: 芦高 恵美子