同步化放电在三叉神经痛中的作用及其Cx43-EAATs的分子调控机制

Trigeminal neuralgia (TN) occurs intermittently with a severe breakthrough pain. The incident rate of TN is approximately 182 /100,000 people. The pathogenesis of TN is still unclear. Some studies indicated that it’s related to the microvascular compression to the peripheral nerves, however, this hypothesis couldn’t fully explain all of these clinical phenomenon. The results from molecular mechanistic studies also can hardly explain the characteristics of breakthrough pain. We have observed the synchronized bursting of different parts of the trigeminal afferent pathway in a rat model of TN from our pre-experiments. The observed synchronization is similar to the EEG of epilepsy reported from the literature and our previous observation of breakthrough pain in animals with metastatic bone tumors. Further studies suggest that it is accompanied by the alterations of the expressions and functions of Cx43 and EAATs (GLAST/GLT-1) . We speculate that the synchronized bursting occurs in the spinal nucleus of trigeminal nerve and related afferent pathway, and it may be regulated by Cx43-EAATs in astrocytes. In order to illuminate the possible mechanism of TN in the cellular and molecular levels as well as in vivo animal models to provide the scientific rationale for clinical intervention, we will study the formation of synchronization and the effect of synchronized bursting on TN as well as the role of astrocytes Cx43 in regulation of GLAST/GLT-1 and calcium wave using the methods of calcium imaging, blind patch clamp, microelectrode array and molecular biology.

三叉神经痛人群发病率约182/10万人，疼痛呈间歇性爆发式发作，异常剧烈，发病机制不清楚。研究认为其发病与微血管压迫神经有关，但不足以解释其临床现象，相关分子机制研究也未能明确解释其爆发式发作的特点。我们预实验观察到三叉神经痛发作时其传入通路不同部位发生了同步化放电，与文献报道的癫痫发作及我们前期骨转移癌爆发痛研究中观察到的电活动类似；进一步实验显示这种同步化放电与Cx43、EAATs的表达及功能改变相关。我们推断：三叉神经痛发作时三叉神经脊束核及相关传入通路发生同步化放电，这种电活动受星形胶质细胞Cx43-EAATs的调控。本研究拟运用钙成像、电生理以及分子生物学等方法，研究神经元同步化放电在三叉神经痛中的作用，探讨星形胶质细胞Cx43调控EAATs和钙波活动影响神经元同步化放电的分子机理，从整体、细胞及分子水平阐明三叉神经痛的发生机制，为临床干预提供依据。

三叉神经痛是一种面部慢性疼痛疾病，疼痛程度剧烈，发病率随着年龄增加而上升，对患者的生活质量产生极大的影响，并且存在复发和耐药的特点，给临床治疗带来困难。我们在前期研究中发现三叉神经痛有爆发式的发作特点，可能与神经元的同步化活动有关。在该项目的研究过程中，我们建立眶下神经慢性缩窄损伤的三叉神经痛大鼠模型，采用分子生物学、电生理以及钙成像等观察手段，从分子、细胞、整体等不同层面对Cx-43、GLT-1在大鼠延髓背角神经元电活动、神经元-胶质细胞相互作用等过程中的作用进行了深入探究，结果显示，三叉神经痛模型大鼠出现延髓背角Cx43表达上调和GLT-1表达下调，头孢曲松钠治疗可以通过上调GLT-1表达缓解CCI模型大鼠的疼痛，GLT-1通过参与延髓背角突触时空可塑性的调节影响神经元网络的同步化活动，此外，GLT-1、Cx-43还通过影响星形胶质细胞激活的方式参与胶质细胞-神经元相互作用，从而影响疼痛信息在初级中枢的整合。研究结果证实了谷氨酸转运体功能异常参与了突触网络可塑性以及神经元同步化活动的调节，并且揭示了胶质细胞钙活动是其作用的重要方式，为进一步的研究提供了理论依据。该研究结果提示，类似于头孢曲松钠的谷氨酸转运体调节剂有望应用于三叉神经痛的治疗。