NCX在神经病理性疼痛发病的作用和机制的研究

The pathogenesis of neuropathic pain mechanism is unknown, treatment is very difficult. Ca2+ plays an important role in the course of neuropathic pain,which is directly involved in the releasing of neuroransmitters in nerve endings. Ca2+ is also a second messenger that can lead to sensorium sensitization by regulating the activity of glial cells through MAPKs pathways. Sodium-calcium exchanger (NCX) is an important transporter in regulating the intracellular and extracellular Ca2+ concentration. In vitro study reported that NCX inhibitors can inhibit the phosphorylation of MAPKs (ERK, JNK, P38) in glial cell. Our preliminary results showed that intrathecal injection of NCX inhibitors can reverse the neuropathic pain, and NCX expression in the spinal dorsal horn astrocytes and DRG neurons is confirmed. Therefore, it's worth discussing the mechanisms of NCX in neuropathic pain. In this study, we use in vivo and in vitro experiments to explore the relationship between the change of NCX and MAPKs signaling pathways and pain-related inflammatory factors in neuropathic pain; NCX regulation mechanisms of glial cell activity; NCX in DRG neurons' function, and its' regulation of sensory nerve fibers in peripheral neurotransmitter releasing mechanism.It will provide a new theoretical basis for the treatment of neuropathic pain.

神经病理性疼痛发病机制不明，治疗棘手。Ca2+在其发病过程中起重要作用，直接参与神经末梢递质释放过程；Ca2+又作为第二信使，通过MAPKs等通路调节胶质细胞的活性，引起感觉中枢敏化。钠钙交换蛋白（NCX）是调节细胞内外Ca2+浓度的重要转运体。离体实验报道NCX抑制剂可抑制胶质细胞MAPKs(ERK、JNK、P38)的磷酸化。我们的前期研究结果显示鞘内注射NCX抑制剂存在抗神经病理性疼痛作用，并证实NCX表达于脊髓背角星型胶质细胞以及DRG的神经元胞体。因此，NCX在神经病理性疼痛的作用和机制值得深入探讨。本研究拟采用在体和离体实验的方法，探讨神经病理性疼痛中NCX的改变与MAPKs信号通路和疼痛相关炎症因子的关系；NCX调控胶质细胞活性的机制；NCX在DRG神经元的功能，及其调节感觉神经纤维末梢递质释放的机制。为治疗神经病理性疼痛提供新的理论依据。

神经病理性疼痛发病机制目前仍不明确，缺乏有效的治疗药物和方法。我们过去的研究发现鞘内注射哇巴因对神经病理性疼痛有良好的治疗作用，哇巴因同时具有抑制钠钙交换蛋白和钠钾交换蛋白的作用。其中钠钙交换蛋白（NCX）是生物体内调节细胞内外Ca2+浓度的重要转运体。Ca2+在神经病理性疼痛形成过程中起重要作用，直接参与神经末梢递质释放过程；也作为第二信使，通过 MAPKs 等通路调节细胞的活性，引起感觉中枢敏化。前期研究结果显示鞘内注射NCX抑制剂存在抗神经病理性疼痛作用，并发现NCX 表达于脊髓背根神经节的神经元胞体。因此本研究采用在体和离体实验的方法探讨神经病理性疼痛中NCX的作用，及其与上游炎性因子、下游信号通路之间的关系；发现在神经病理性疼痛中DRG神经元的NCX在炎性因子的作用下出现功能变化，引起细胞内钙离子增加，并通过激活下游的ERK通路磷酸化，引起DRG神经元敏感性增加，导致痛觉过敏。该研究结果对神经病理性疼痛的研究供了新的理论依据和治疗靶点。