Cortical Mechanisms of Headache: Beyond CSD

项目摘要 大量间接证据现在强烈支持这样一种观点，即伤害性感觉通路 支配颅内脑膜(三叉神经血管系统)参与了一些 临床上出现的各种头痛，包括偏头痛。这条感官通路的基本特性有 已经在动物实验中进行了详细的研究，但还不太清楚这条途径是如何被激活的 在临床上出现头痛发作时。一项领先的研究已经提供了证据支持 偏头痛的皮质扩散性抑制(CSD)理论，包括三叉神经血管的最新发现 动物CSD诱导后的神经元激活。然而，偏头痛患者的CSD研究是 一定有些轶事，因为CSD不能用常规方法在人类身上检测到，所以它是 不知道它多久发生一次，或者是什么原因导致它自发出现。作为进一步探索的新途径 可以引发头痛的机制和皮质病理生理学的潜在作用，我们现在提出 在一种常见类型的三叉神经痛动物模型中研究三叉神经血管神经元激活的机制 在人类中被很好地描述和深入研究的皮质病理生理学：皮质癫痫。基于 临床观察，癫痫发作后常伴有头痛，其特征类似于偏头痛。 假设癫痫发作可以激活三叉神经血管系统。因此，我们建议测试 这一假说，并以癫痫发作为模型，进一步研究大脑皮质 过程可以影响三叉神经血管系统，其目的如下：(1)使用单一单位 为了监测三叉神经节中一级硬脑膜敏感神经元的活动变化，我们将 检验化学致痫可引起硬脑膜激活和/或敏化的假说 痛觉感受器。癫痫诱发效应也将在不支配三叉神经节的神经元中进行检测。 硬脑膜。(2)采用单单位记录的方法，观察了大鼠双侧大脑中隔核内二级硬膜反应神经元的活动变化。 下面将检查上颈椎和延髓背角的浅层和深层 麻醉大鼠的癫痫发作。与目标1一样，缺乏硬脑膜反应的神经元也将被研究。数据 分析将确定癫痫发作引起的活动变化的潜伏期、持续时间和幅度，以及 比较硬脑膜敏感神经元和非硬脑膜敏感神经元的癫痫发作效应。实验将验证这一假设 神经元的激活将由枕叶而不是顶叶皮质部位的局灶性癫痫产生，平行 出现后遗症头痛的区域选择性模式。为了确定是否 癫痫诱发放电起源于硬脑膜感受野内的终末，利多卡因将应用于 在癫痫发作高峰期间，在癫痫发作诱导之前或之后的硬脑膜- 诱发放电。

Project Summary A large body of indirect evidence now strongly supports the idea that the nociceptive sensory pathway that innervates the intracranial meninges (the trigeminovascular system) is involved in the generation of some types of clinically occurring headaches, including migraine. The basic properties of this sensory pathway have been studied in detail in animal studies, but it is not yet well understood how this pathway becomes activated during a clinically occurring headache attack. One leading line of research has provided evidence in support of the CSD (cortical spreading depression) theory of migraine, including the recent findings of trigeminovascular neuron activation following CSD induction in animals. However, the study of CSD in migraine patients is necessarily somewhat anecdotal because CSD cannot be detected by routine methods in humans, and so it is not known how often it occurs, or what causes it to arise spontaneously. As a new avenue to further explore the mechanisms that can trigger headache and the potential role of cortical pathophysiology, we now propose to examine mechanisms of trigeminovascular neuron activation in an animal model of a common type of cortical pathophysiology that is well described and intensively studied in humans: cortical seizure. Based on the clinical observation that seizures are commonly followed by headache with features similar to migraine, we hypothesize that seizure can produce activation of the trigeminovascular system. We therefore propose to test this hypothesis, and to use seizure as a model to further investigate the mechanisms by which cortical processes can influence the trigeminovascular system, in the following Aims: (1) Employing single-unit recording to monitor changes in activity of first-order dura-sensitive neurons in the trigeminal ganglion, we will test the hypothesis that chemically-induced seizures can induce activation and/or sensitization of dural nociceptors. Seizure-induced effects will also be examined in trigeminal ganglion neurons that do not innervate the dura. (2) Using single-unit recording, changes in activity of second-order dural-responsive neurons in the superficial and deep laminae of the upper cervical and medullary dorsal horn will be examined following seizures in anesthetized rats. As in Aim 1, neurons that lack a dural response will also be studied. Data analysis will determine the latency, duration, and magnitude of changes in activity induced by seizure, and compare the seizure effects in dura-sensitive vs. dura-insensitive neurons. Experiments will test the hypothesis that neuronal activation will be produced by focal seizure in occipital but not parietal cortical sites, paralleling the regionally selective pattern found for the occurrence of postictal headache. In order to determine whether the seizure-induced discharge originates in terminals within the dural receptive field, lidocaine will be applied to the dura either prior to seizure induction or following seizure induction during the period of peak seizure- induced discharge.