TRESK通过Ras/MAPK信号通路参与神经病理性疼痛的机制研究

Neuropathic pain is a serious problem affecting human health, but there is a lack of effective treatment at present. Researching into the mechanism of neuropathic pain is of great significance. TRESK, One of the two pore potassium ion channels, which was found in recent years, is expressed abundantly in dorsal root ganglia, and represents the most important background potassium channel.At present, our basic researches have demonstrated that the TRESK in dorsal root gaanglia plays an important role in the process of neuropathic pain. Ras/MAPK signal transduction pathway is the information transmission pathway which generated the effect of intracellular transcription and translation from the extracellular signals. It has been reported in our previous work that MAPK plays an important role in the regulation of pain sensitization of the pathophysiologic changes. Also,the related literature also suggests that Ras is closely related to the Ca2+ signal adjusted by TRESK. Using lentiviral vector with RNA interference and RNA over expression,we discussed TRESK involved in the mechanism of neuropathic pain through Ras/MAPK signal transduction pathwaythe by means of the experimental technique of animal ethology, cell biology and molecular biology. Hopefully, it can provide a theoretical basis and new therapeutic target for neuropathic pain.

神经病理性疼痛是困扰人类健康的严重问题，目前尚缺乏有效的临床治疗措施。探讨神经病理性疼痛的作用机制具有重要意义。 TRESK是近年来发现的一个双孔钾离子通道，在背根神经节大量表达，主要功能为编码背景钾电流。我们的基础研究已证明：背根神经节的TRESK在神经病理性疼痛的发生、发展中起着重要作用。 Ras/MAPK信号通路是将胞外刺激信号转换至胞核内，产生转录和翻译后效应的信息传递通路。我们的前期工作已证明了MAPK信号通路在疼痛敏化调控的病理生理变化中的重要作用，而且相关文献也提示:Ras与TRESK调节的Ca2+信号密切相关。 本研究以RNA干扰和RNA过表达的慢病毒载体为工具，通过动物行为学、细胞生物学和分子生物学的实验方法，探讨背根神经节的TRESK通过Ras/MAPK信号通路参与神经病理性疼痛的作用机制,为神经病理性疼痛的治疗提供理论基础及新的治疗靶点。

神经病理性疼痛的机制复杂，目前并未完全阐明清楚。双孔钾离子通道TRESK是背根神经节(DRG)主要表达的钾离子通道。我们前期的研究发现，在神经病理性疼痛模型中，MAPK信号通路可能参与了TRESK介导的神经病理性疼痛机制。因此，我们研究了在神经病理性疼痛动物模型中，TRESK是否通过MAPK信号通路介导炎性反应和细胞凋亡参与神经病理性疼痛。另外，脊髓水平的TRESK如何分布和表达目前并不清楚，因此我们进一步确定了TRESK的细胞表达以及在脊髓水平如何传递疼痛信号。本研究基本完成计划书的研究目标。课题试验双向证明了脊髓水平TRESK在神经病理性疼痛中的重要作用：神经病理性疼痛引起脊髓水平的TRESK下调，而脊髓水平TRESK下调可诱发机械痛敏的发生；另外，研究证实了脊髓水平MAPK信号通路（p38、ERK）参与了TRESK介导的神经病理性疼痛的下游机制；最后，我们的研究还证明了脊髓神经元TRESK通过缝隙连接调节胶质细胞激活参与神经病理性疼痛机制。这些结果表明TRESK是治疗神经病理性疼痛的一个重要靶点，对今后的靶向治疗具有重要临床意义。