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障碍，没有持续有效的治疗干预措施。它也是最普遍的疼痛障碍之一，折磨着多达10%的普通成年人和18%的女性。因此，确定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脉管系统的初级传入神经元是偏头痛发作疼痛的来源。因此，本建议的重点是可以影响传入活动的硬脑膜成分。这些成分包括硬脑膜和硬脑膜脉管系统中的常驻免疫细胞和募集免疫细胞。我们还将研究事件本身。我们建议利用偏头痛的两个独特特征作为一种手段来确定偏头痛发作的机制。一是压力是偏头痛发作的最常见诱因。第二，偏头痛发作发生在压力结束后的放松阶段。我们提出，硬脑膜中的交感神经节后神经元（SPGN）作为应激和偏头痛之间的联系，因为它们是应激反应系统的关键组成部分，硬脑膜受SPGN末端的神经支配，并且研究的所有三种硬脑膜成分都受SPGN末端释放的介质的调节。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更高，而且性激素，特别是雌激素，共同调节有待研究的每种硬脑膜成分。因此，该提议的中心假设是，压力驱动硬脑膜免疫细胞、脉管系统和初级传入神经的调节发生性和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硬脑膜内常驻和募集免疫细胞的影响。在第二部分中，我们将确定性别和持续应激对spgn依赖性硬脑膜脉管系统调节的影响。第三，我们将确定性别和持续应激对硬脑膜传入和硬脑膜传入兴奋性中电压门控Ca2+电流的spn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，硬脑膜是大脑健康的关键结构，而且还将为治疗偏头痛提供新的方法，使其能够完全预防发作。

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.