Alteration of the cell adhesion molecule L1 expression in a specific subset of primary afferent neurons contributes to 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。本研究表明，周围神经损伤诱导大鼠背根神经节（DRG）和脊髓L1-CAM转录后动态改变。坐骨神经横断（SCNT）可改变L1-CAM蛋白的表达，但不能改变L1-CAM mRNA的表达。在DRG中，SCNT诱导L1-CAM积聚到体细胞表面，导致许多无髓鞘c纤维神经元形成免疫反应性（ir）环结构。这些具有L1-CAM ir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全长L1-CAM增加，L1-CAM片段减少。SCNT后，背角L1-CAM ir谱显示主要在I-II层的突触前区域增加，延迟发作，并与生长相关蛋白43共定位。与DRG相比，SCNT增加了L1-CAM蛋白水解80 kDa片段，减少了L1-CAM全长。鞘内注射L1-CAM细胞外结构域抗体可抑制损伤DRG神经元p38 MAPK的激活和L1-CAM ir环状结构的出现。此外，鞘内注射抗体抑制细胞外L1-CAM结合可抑制部分坐骨神经横断引起的机械性异痛和热痛觉过敏。综上所述，这些数据表明伤害性通路L1-CAM的改变可能是神经性疼痛的一个重要病理机制。

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.