中脑导水管周围灰质网络在癫痫和偏头痛交互影响中的作用

The interacting relationship between epilepsy and migraine is attracting more and more attention. Dysfunction of the midbrain ventrolateral periaqueductal gray (vPAG), a key structure of descending inhibitory modulation of pain, is one of the major pathogenic events in migraine. Recent studies indicate that the excitatory transduction from vPAG can activate the pedunculopontine nucleus (PPN) whose activation has a significant anti-epileptic effect. In combination with the fact of the interacting relationship between epilepsy and migraine and the pathogenic theories of them, we raise the following hypothesis: In chronic epilepsy, recurrent attacks of seizures lead to neuronal loss and function disturbance of the vPAG, resulting in attenuation of the inhibitory pain modulation and thus causing the susceptibility of migraine headache attacking. Simutaneously, the neuronal loss and function disturbance of the vPAG lead to the weakening of the PPN-activating signal from the vPAG and thus causing the susceptibility of seizure attacking. Conversely, the neuronal loss and function disturbance of the vPAG caused by recurrent attacks of migraine headaches will deteriorate the migraine headache attacking, and will simutaneously facilitate the seizure attacking due to the weakened PPN-activating signal from the vPAG structurely and functionaly impaired by the chronic headache attacks. In the current study, measures of stereotactic lesion to specific gray nucleus, neural fiber retrograde tracing, electroencephalogram and behavior recording, imaging technique are employed to investigate the neuronal injury in the vPAG, the impairment of the connectedness between vPAG and PPN and their retroaction on epileptic seizure as well as on migraine/hyperalgesia, preliminarily clarifying the role of the vPAG-PPN pathway in the interacting relationship between epilepsy and migraine, and thus exploring a novel direction for future co-treatment of epilepsy and migraine.

癫痫与偏头痛的交互影响关系受到越来越多的重视。中脑腹侧导水管周围灰质（vPAG）作为下行抑制性痛觉调节的关键核团，其功能受损是偏头痛的重要病理原因。新近研究表明vPAG的兴奋冲动能够激活脑桥的脚桥核（PPN），后者的激活则有显著的抗癫痫作用。结合癫痫和偏头痛的发病理论及其交互作用关系，我们假说：慢性癫痫发作致vPAG神经元脱失和功能受损，痛觉抑制减弱，引发偏头痛，同时致vPAG-PPN兴奋传导下降，从而导致癫痫发作加重；反之，偏头痛反复发作致vPAG受损，恶化偏头痛，同时致vPAG-PPN兴奋传导下降，也导致了癫痫发作的加重。本研究应用立体定向核团毁损、神经逆向示踪、脑电、脑场电位及行为记录的方法，观察癫痫和偏头痛/痛觉过敏所致vPAG结构及vPAG-PPN连接强度受损及其反馈效应，初步明确vPAG-PPN传导通路在癫痫和偏头痛交互影响中的作用，为未来癫痫和偏头痛的共治探索一新的方向。

项目背景：癫痫与偏头痛属交互影响的关系，癫痫可以促发偏头痛而偏头痛则是癫痫发作的危险因子且阻碍了癫痫的治疗。有研究表明腹侧中脑导水管周围灰质（vlPAG）在偏头痛病理生理中起着关键作用且可能与癫痫病理有关。另外，有研究表明脚桥核（PPN）可能参与了癫痫的内在压制作用。因此，我们认为vlPAG可能通过脚桥核这一传导通路对癫痫和痛觉产生影响。.主要研究内容：观察了癫痫持续状态后自发性癫痫发作形成过程中的vlPAG结构受损情况。通过神经化学部分损毁vlPAG观察其对自发性癫痫发作和痛觉阈值的影响以初步明确vlPAG在癫痫中的作用及其在癫痫共患偏头痛中的作用。反之，通过对vlPAG的神经保护以观察其对癫痫发作和痛觉阈值的影响。通过脑立体定位仪将神经纤维逆向示踪剂荧光金（FG）注入大鼠脑的脚桥核PPN区，在vlPAG去检测FG与C-Fos及vGlut1的共表达，以研究动物模型癫痫和偏头痛及二者共患病对vlPAG-PPN通路的兴奋性传导活性的影响；通过功能磁共振的方法研究癫痫和偏头痛患者及二者共患病患者的vlPAG-PPN通路的功能连接改变。 .重要结果、关键数据及其科学意：①SE诱导的癫痫发生过程中伴随着vlPAG内神经元丢失及兴奋性和抑制性神经传递的改变。另一方面，对vlPAG的神经化学损伤可使脑电图中自发性发作事件的频率和持续时间以及癫痫样发作间峰放电的频率增加而癫痫大鼠的疼痛阈值降低。这表明疼痛调节结构vlPAG参与了癫痫的确了BDNF在vlPAG区持续高表达对癫痫鼠vlPAG、皮层和海马的神经保护发病机制。这提示vlPAG网络的改变是癫痫和偏头痛相互作用共病关系的潜在机制。②通过BDNF基因导入明作用，同时发现其对癫痫鼠癫痫发作、脑电癫痫样放电及痛觉敏感性增高的改善作用。慢性癫痫形成过程中和慢性偏头痛模型中伴随vlPAG-PPN神经传导的弱化，基因导入BDNF在vlPAG区持续高表达可改善慢性癫痫所致vlPAG-PPN神经传导的弱化。这提示vlPAG-PPN神经传导受损改变可能是癫痫和偏头痛相互作用共病关系的潜在机制；功能磁共振研究发现癫痫和偏头痛患者及二者共患病患者的vlPAG-PPN通路的功能连接弱化改变，尤以二者共患病患者更为显著。