TNF-α enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury
TNF-α enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury
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DOI：
10.1016/j.expneurol.2010.11.017
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发表时间：
2011-02-01
影响因子：
5.3
通讯作者：
Liu, Xian-Guo
中科院分区：
文献类型：
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作者：
Chen, Xi;Pang, Rui-Ping;Liu, Xian-Guo
在未损伤的背根神经节（DRG）神经元中观察到的异位放电被归因于电压门控钠通道（VGSC）的功能改变。这种机制可能是重要的神经性疼痛的发展。然而，神经损伤后VGSC功能调节的病理生理学基础在很大程度上是未知的。在这里，我们研究了这个问题，使用选择性腰5腹根横断（L5-VRT）模型，其中背根神经节（DRG）神经元保持完整。我们发现，L5-VRT增加TTX敏感的Na通道的电流密度，以及在Nav1.8的电流，但不是Nav1.9通道在未受伤的DRG神经元。L5-VRT后DRG神经元动作电位阈值降低，放电频率增加。由于我们发现L5-VRT后脑脊液（CSF）和DRG组织中肿瘤坏死因子-α（TNF-α）水平升高，我们测试了TNF-α升高是否可能导致钠通道的变化。事实上，重组大鼠TNF（rrTNF）增强TTX-S和Nav1.8在培养的DRG神经元的电流密度的剂量依赖性。此外，小鼠中TNF受体1（TNFR-1）的基因缺失减轻了L5-VRT诱导的机械性异常性疼痛，并阻止了DRG神经元钠电流的增加。这些数据表明，神经损伤后未受伤的DRG神经元中钠电流的增加可能是由TNF-α的过度产生介导的。(C)2010年爱思唯尔公司All rights reserved.
The ectopic discharges observed in uninjured dorsal root ganglion (DRG) neurons following various lesions of spinal nerves have been attributed to functional alterations of voltage-gated sodium channels (VGSCs). Such mechanisms may be important for the development of neuropathic pain. However, the pathophysiology underlying the functional modulation of VGSCs following nerve injury is largely unknown. Here, we studied this issue with use of a selective lumbar 5 ventral root transection (L5-VRT) model, in which dorsal root ganglion (DRG) neurons remain intact. We found that the L5-VRT increased the current densities of TTX-sensitive Na channels as well as currents in Nav1.8, but not Nav1.9 channels in uninjured DRG neurons. The thresholds of action potentials decreased and firing rates increased in DRG neurons following L5-VRT. As we found that levels of tumor necrosis factor-alpha (TNF-alpha) increased in cerebrospinal fluid (CSF) and in DRG tissue after L5-VRT, we tested whether the increased TNF-alpha might result in the changes in sodium channels. Indeed, recombinant rat TNF (rrTNF) enhanced the current densities of TTX-S and Nav1.8 in cultured DRG neurons dose-dependently. Furthermore, genetic deletion of TNF receptor 1 (TNFR-1) in mice attenuated the mechanical allodynia and prevented the increase in sodium currents in DRG neurons induced by L5-VRT. These data suggest that the increase in sodium currents in uninjured DRG neurons following nerve injury might be mediated by over-production of TNF-alpha. (C) 2010 Elsevier Inc. All rights reserved.