三叉神经痛发作的诱发簇放电机制

Trigeminal neuralgia (TN) is a kind of intractable neuropathic pain. Despite of the fact that the damaged trigeminal ganglion (TG) is the source of the neuropathic pain signal, identification of its characteristics and its mechanism of allodynia has been unsuccessful which leading to the ineffective analgesic drugs in clinic. Our previous research has reported the exist of excitability classification in rat mesencephalic V (Mes V) neurons. The excitation transition could happen by manipulating the dynamic proportion of I(4-AP) and INap.Recently,the evoked bursting (EB) was reported to be the allodynia signal in injured dorsal root ganglion (DRG) neurons which has the similar effect in evoking the TN episode events. Based on those studies we assume that excitability classification of TG neuron could transform each other under the condition of inflammation and injured state, which make the proportion of class 2 excitability neuron increase significantly, so resulting the increase of probability of EB.In this way, TG become an ectopic pacemaker of allodynia signal. When stimulate the peripheral receptive field, multiple evoked bursting outbreak simultaneously within the TG, spread to the central nervous system and cause severe pain. In this study, using animal model of infraorbital nerve chronic constriction injury (ION-CCI), behavioral test, electrophysiological technique, molecular biology and pharmacological techniques were all used to get this purpose. We are planning to explore the characteristic of excitatory transformation, ion and molecular mechanisms of TN, to clarify the nature of the allodynia signal. Which might provide a specific molecular target for inhibiting allodynia signal of TN.

三叉神经痛（TN）是一种难治的神经病理痛。受损三叉神经节（TG）是触诱发痛信号的来源，至今尚未识别其特征及产生机制，临床缺乏有效的镇痛药物。我们近期在三叉神经中脑核观察到神经元兴奋性的分型、转型及其相关离子通道比例的动态变化；并在受损背根节发现诱发簇放电（EB）是引起触诱发痛发作的一种电活动信号。据此我们设想：在炎症或受损条件下，TG内神经元兴奋性类型发生转变，即产生簇放电的2型神经元数目显著增多，使得EB出现的概率增加，成为触诱发痛信号的异位起搏点。当外周感受野受到触压等非痛刺激时，TG内多个EB同步爆发，传入中枢引起剧烈疼痛。本项目拟利用眶下神经慢性缩窄环术TN动物模型，通过痛行为学、电生理学及分子生物学等技术揭示TN发作的规律、特征、兴奋性转型、离子通道及分子机制，阐明TN发作的本质过程，为临床筛选抑制触诱发痛发作的理想镇痛药物提供特异的分子靶点。

三叉神经痛（TN）是一种难治的神经病理痛。受损三叉神经节（TG）是触诱发痛信号的来源，至今尚未识别其特征及产生机制，临床缺乏有效的镇痛药物。我们利用眶下神经慢性缩窄环术TN动物（ION-CCI）模型，通过痛行为学、电生理学及分子生物学等技术揭示TN发作的规律、特征、兴奋性转型、离子通道及分子机制。结果发现：1)自ION-CCI术后第1天起大鼠面部机械痛阈即明显下降，术后12-14天达到最低值，之后轻度上升上升，但仍≦2g。2)正常对照组TG上2类兴奋性神经元和3类兴奋性神经元所占比例分别为24.2%和75.8%；而在ION-CCI模型组TG上二者比例分别为41.3%和58.7%，提示TG受损后2类兴奋性神经元数目异常增多（P＜0.05）。3) 兴奋性神经元之间的相互转型现象：2类兴奋性神经元在TTX作用下转型为3类兴奋性神经元；3类兴奋性神经元在4-AP作用下转型为2类兴奋性神经元。4）正常对照组和ION-CCI模型组TG上的2类兴奋性神经元中I4-AP含量基本相同，INaP的含量基本相同；3类兴奋性神经元中I4-AP含量基本相同，INaP的含量基本相同。5) 当除极化水平≧ - 56mv时，I4-AP在2类兴奋性神经元中的平均幅值明显地小于在3类兴奋性神经元中的（P＜0.05）；而INaP在2类兴奋性神经元中的平均幅值明显地大于在3类兴奋性神经元中的（P＜0.05）。6）ION-CCI模型组TG上Kv1.2的mRNA含量较结扎对侧、假手术组及空白组明显下调；Nav1.3的mRNA含量较结扎对侧、假手术组及空白组明显上调。7) ION-CCI模型眶下神经结扎后，TG上Kv1.2的蛋白含量较结扎对侧、假手术组及空白组明显减少；Nav1.3的蛋白含量较结扎对侧、假手术组及空白组明显增多。该结果将痛行为学、离子通道及分子生物学机制紧密结合，深入阐明触摸刺激何以引起TN发作的细胞分子机制，阐明TN发作的本质过程，重新认识神经元兴奋性分类与转型的复杂性变化规律，为临床筛选抑制触诱发痛发作的理想镇痛药物提供特异的分子靶点，进而为临床阻止TN的发作提供新的策略导向。