Mechanisms of Migraine

偏头痛的发病机制 偏头痛是一种使人衰弱的阵发性疼痛障碍，目前尚无一贯有效的治疗方法。 治疗性干预。它也是最普遍的疼痛障碍之一，困扰着高达10%的人 占成年总人口的比例和18%的女性。确定可持续发展的新方法 因此，偏头痛的治疗意义重大。 普遍证据表明，支配硬脑膜的初级传入神经元 和硬脑膜血管是偏头痛发作疼痛的根源。目前的建议是 因此，重点研究了可以影响传入活动的硬脑膜成分。这些组件 包括硬脑膜和硬脑膜血管中的常驻和重新招募的免疫细胞。我们还将研究 传入者自己。我们建议利用偏头痛的两个独特特征作为一种手段 确定导致偏头痛发作的机制。其一，压力是最大的 偏头痛发作的常见诱因。第二，偏头痛发作发生在放松阶段。 在压力结束后。我们认为硬脑膜中的交感节后神经元(SPGN) 作为压力和偏头痛之间的纽带，因为它们是压力的关键组成部分 反应系统，硬脑膜主要由SPGN终末和所有三个硬脑膜成分支配 被研究的是由SPGN终末释放的介质调节的。最后，我们还提出， 性别是影响压力和偏头痛之间联系的关键因素，因为 女性偏头痛的患病率以及性腺激素，特别是雌激素与偏头痛的相关性 调节待研究的每个硬脑膜成分。因此，这一提议的中心假设是 这种压力驱使硬脑膜免疫调节的性别和SPGN依赖的变化 细胞、血管系统和初级传入，为偏头痛的发生奠定了基础 进攻。这一假设将在三个具体目标下描述的实验中得到验证。首先， 我们将确定性别、SPGN神经支配和持续应激对居民和 在硬脑膜中招募免疫细胞。在第二节中，我们将确定性爱和持久性的影响 应激对SPGN依赖的硬脑膜血管系统的调节。在第三部分中，我们将确定 性别和持续应激对大鼠心肌细胞SPGN依赖性电压门控性钙电流的影响 硬脑膜传入和硬脑膜传入兴奋性。拟议中的实验不仅将提供有价值的 对硬脑膜神经生物学的洞察，这是一种对大脑健康至关重要的结构，但建议 治疗偏头痛的新方法能够完全预防偏头痛发作。

Mechanisms of Migraine Migraine is a debilitating episodic pain disorder for which there are no consistently effective therapeutic interventions. It is also one of the most prevalent pain disorders afflicting as many as 10% of the general adult population and 18% of women. Identification of novel approaches for the treatment of migraine is therefore highly significant. The prevailing weight of evidence indicates that the primary afferent neurons innervating the dura and dural vasculature are the source of the pain of a migraine attack. The present proposal is therefore focused on components of the dura that can influence afferent activity. These components include resident and recruited immune cells in the dura and the dural vasculature. We will also study the afferents themselves. We have proposed to exploit two unique features of migraine as a means to identify mechanisms that enable the initiation of a migraine attack. One is that stress is the most common trigger of a migraine attack. A second is that migraine attacks occur during relaxation phase after stress has ended. We propose that sympathetic post-ganglionic neurons (SPGN) in the dura serve as a link between stress and migraine because they are a critical component of the stress response system, the dura is heavily innervated by SPGN terminals, and all three dural components to be studied are regulated by mediators released from SPGN terminals. Finally, we also propose that sex is a critical factor that influences the link between stress and migraine because of the higher prevalence of migraine in women and the fact that gonadal hormones, in particular estrogens co- regulate each of the dural components to be studied. Thus, the central hypothesis of this proposal is that that stress drives sex- and SPGN-dependent changes in the regulation of dural immune cells, vasculature and primary afferents, that set the stage for the initiation of a migraine attack. This hypothesis will be tested in experiments described under three specific aims. In the first, we will determine the impact of sex, SPGN innervation, and persistent stress on resident and recruited immune cells in the dura. In the second, we will determine the impact of sex and persistent stress on SPGN-dependent regulation of the dural vasculature. In the third, we will determine the impact of sex and persistent stress on SPGN-dependent changes in voltage-gated Ca2+ currents in dural afferents and dural afferent excitability. The proposed experiments will not only provide valuable insight into the neurobiology of the dura, a structure critical for the health of the brain, but suggest novel approaches for the treatment of migraine enabling the prevention an attack altogether.