Mechanisms of Migraine

描述（由申请人提供）：偏头痛是一种使人衰弱的发作性疼痛疾病，目前尚无持续有效的治疗干预措施。它也是最普遍的疼痛疾病之一，困扰着多达10%的普通成年人和18%的女性。因此，识别治疗偏头痛的新方法是非常重要的。 目前的证据表明，支配硬脑膜和硬脑膜血管系统的初级传入神经元是偏头痛发作疼痛的来源。因此，目前的建议是集中在硬脑膜的组成部分，可以影响传入活动。这些成分包括硬脑膜和硬脑膜脉管系统中的驻留和募集的免疫细胞。我们还将研究传入神经本身。我们已经提出利用偏头痛的两个独特的功能作为一种手段，以确定机制，使偏头痛发作的开始。一个是压力是偏头痛发作最常见的诱因。第二种是偏头痛发作发生在压力结束后的放松阶段。我们建议，交感神经节后神经元（SPGN）在硬脑膜作为压力和偏头痛之间的联系，因为他们是一个重要组成部分的压力反应系统，硬脑膜是严重受SPGN终端，和所有三个硬脑膜组件进行研究的调节介质从SPGN终端释放。最后，我们还提出，性别是影响压力和偏头痛之间联系的一个关键因素，因为女性偏头痛的患病率较高，而且性腺激素，特别是雌激素共同调节每个待研究的硬脑膜成分。因此，该提议的中心假设是，压力驱动硬脑膜免疫细胞、血管系统和初级传入神经调节中的性别和SPGN依赖性变化，这为偏头痛发作的开始奠定了基础。这一假设将在三个具体目标下描述的实验中进行测试。首先，我们将确定性别、SPGN神经支配和持续压力对硬脑膜中常驻和招募的免疫细胞的影响。在第二部分中，我们将确定性别和持续压力对硬脑膜血管系统SPGN依赖性调节的影响。在第三部分，我们将确定性别和持续应激对硬脑膜传入神经和硬脑膜传入神经兴奋性中电压门控性Ca2+电流的SPGN依赖性变化的影响。拟议的实验不仅将为硬脑膜的神经生物学提供有价值的见解，硬脑膜是一种对大脑健康至关重要的结构，而且还提出了治疗偏头痛的新方法，从而能够完全预防发作。

DESCRIPTION (provided by applicant): 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.