Alteration of the cell adhesion molecule L1 expression in a specific subset of primary afferent neurons contributes to neuropathic pain

初级传入神经元特定亚群中细胞粘附分子 L1 表达的改变导致神经性疼痛

• 批准号: 18500269
• 负责人: YAMANAKA Hiroki
• 金额: $ 2.57万
• 依托单位: Hyogo College of Medicine
• 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-18500269/
• 关键词: neurpnathic pain; cell adhesion molecules; L1-CAM; dorsal root gangliae; dorsal horn; synapse; plasticuty; post transcriptional regulation; シナプス可塑性; MAP kinase; 翻訳後修飾; cell adhesion; proteolysis; Dorsal root gamglia; dorsal horn synapse; sy

The cell adhesion molecule L1 (L1-CAM) plays important functional roles in the developing and adult nervous system. Here we show that peripheral nerve injury induced dynamic post-transcriptional alteration of L1-CAM in the rat dorsal root ganglia (DRG) and spinal cord. Sciatic nerve transection (SCNT) changed the expression of L1-CAM protein but not L1-CAM mRNA. In DRG, SCNT induced accumulation of the L1-CAM into surface of somata, which resulted in the formation of immunoreactive (ir) ring structures in a number of unmyelinated C-fiber neurons. These neurons with L1-CAM ir ring structures were heavily co-localized with phosphorylated p38 MAPK. Western blot analysis revealed the increase of full-length L1-CAM and decrease of fragments of L1-CAM after SCNT in DRG. Following SCNT, L1-CAM ir profiles in the dorsal horn showed an increase mainly in pre-synaptic areas of laminae I-II with a delayed onset and co-localized with growth-associated protein 43. In contrast to DRG, SCNT increased the proteolytic 80 kDa fragment of L1-CAM and decrease of full-length of L1-CAM in the spinal cord. The intrathecal injection of L1-CAM antibody for the extracellular domain of L1-CAM inhibited activation of p38 MAPK and emergence of ring structures of L1-CAM ir in injured DRG neurons. Moreover, inhibition of extracellular L1-CAM binding by intrathecal administration of antibody suppressed the mechanical allodynia and thermal hyperalgesia induced by partial sciatic nerve transection. Collectively, these data suggest that the modification of L1-CAM in nociceptive pathways might be an important pathomechanism of neuropathic pain.

细胞粘附分子L1（L1-CAM）在发育和成人神经系统中起着重要的功能作用。在这里，我们表明，周围神经损伤诱导动态转录后改变L1-CAM在大鼠背根神经节（DRG）和脊髓。坐骨神经切断（SCNT）后L1-CAM蛋白表达改变，但L1-CAM mRNA表达无明显变化。在DRG中，SCNT诱导L1-CAM聚集到胞体表面，导致在一些无髓C纤维神经元中形成免疫反应（ir）环结构。这些具有L1-CAM免疫反应环结构的神经元与磷酸化的p38 MAPK高度共定位。Western blot分析显示，SCNT后DRG中L1-CAM全长表达增加，片段表达减少。SCNT后，L1-CAM免疫反应谱在背角表现出增加，主要是在突触前区的板层I-II延迟发病和共定位与生长相关蛋白43。与DRG相比，SCNT增加了脊髓中L1-CAM的蛋白水解80 kDa片段，并减少了L1-CAM的全长。鞘内注射L1-CAM胞外区抗体可抑制损伤DRG神经元中p38 MAPK的激活和L1-CAM环结构的出现。此外，通过鞘内注射抗体抑制细胞外L1-CAM结合抑制了部分坐骨神经切断引起的机械异常性疼痛和热痛觉过敏。总之，这些数据表明，L1-CAM在伤害性通路中的修饰可能是神经病理性疼痛的重要病理机制。

项目成果

Activation of fibroblast growth factor receptor by axotomy, through downstream p38 in dorsal root ganglion, contributes to neuropathic pain

• DOI: 10.1016/j.neuroscience.2007.08.024
• 发表时间: 2007-11
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: H. Yamanaka;K. Obata;K. Kobayashi;Y. Dai;T. Fukuoka;K. Noguchi

The effect of site and type of nerve injury on the expression of brain-derived neurotrophic factor in the dorsal root ganglion and on neuropathic pain behavior

• DOI: 10.1016/j.neuroscience.2005.10.015
• 发表时间: 2006-12
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: K. Obata;H. Yamanaka;Kimiko Kobayashi;Yi Dai;Toshiyuki Mizushima;Hirokazu Katsura;T. Fukuoka;A. To

Agonist of PAR2 increases painful behavior produced by alpha, beta-methylene adenosine 5'-triphosphate

PAR2 激动剂可增加 α, β-亚甲基腺苷 5-三磷酸产生的疼痛行为

• 期刊: Neuroreport 17
• 作者: Zhu;W. J.;et. al.
• 通讯作者: et. al.

Roles of extracellular signal-regulated protein kinase(ERK) 5 in spinal microglia and primary sensory neurons for neuropathic pain

细胞外信号调节蛋白激酶（ERK）5在脊髓小胶质细胞和初级感觉神经元中对神经性疼痛的作用

• 发表时间: 2007
• 作者: Noguchi;K.
• 通讯作者: K.

Frequency-dependent ERK phosphorylation in spinal neurons by electric stmutation of the sciatic nerve and the role in electrophysiological activity

坐骨神经电刺激导致脊髓神经元频率依赖性 ERK 磷酸化及其在电生理活动中的作用

• 发表时间: 2007
• 期刊: Mol.Pain 3.18
• 作者: Fukui;T.;et. al.
• 通讯作者: et. al.