Estrogen Withdrawal and Dural Mast Cells: Implication for Menstrual Migraine

描述(由申请人提供)：偏头痛主要影响生育年龄的女性，在所有女性偏头痛患者中，近一半的人在月经前后偏头痛发作的频率和严重程度增加。尽管这些与月经相关的偏头痛的机制尚不清楚，但现在认为经前阶段血浆雌激素水平的突然下降是一个关键因素。然而，雌激素停用如何促进月经性偏头痛仍是一种推测。基于对雌性大鼠的初步实验，我们假设生殖激素水平的变化对脑膜伤害性感受器的活动产生调制影响，具体地说，雌激素停用会增加脑膜伤害性感受器对偏头痛刺激的敏感性，如三硝酸甘油(GTN)。我们进一步假设，这种脑膜伤害性感受器活动的增强随后促进了迟发性颅周超敏反应的发展(一种与偏头痛相关的情况)。最后，我们推测，雌激素撤除这种促伤害效应的一个可能机制可能与其对硬脑膜MC的影响有关，后者反过来可以促进脑膜伤害性感受器的激活。我们建议使用体内电生理记录以及行为和组织学技术来测试我们的工作假说。提出了三个具体的目标：目标1是确定雌激素撤退，无论是在发情周期自然发生的还是在去卵巢(OVX)动物实验中诱导的，是否调节脑膜伤害性感受器对注射偏头痛触发分子GTN的反应。目的2研究雌激素撤除对GTN诱发的脑膜伤害性感受器激活的增强作用是否在行为学上表现为脑膜触觉超敏。目的3a通过耗尽MCs或阻断MCs脱颗粒的治疗，研究MCs在雌激素撤除对GTN诱导的脑膜伤害性感受器激活和颅周超敏反应中的作用。目的3b旨在探讨雌激素撤除增强GTN作用的可能机制之一是通过影响硬脑膜MC对GTN的反应而脱颗粒的倾向。综上所述，这些新颖的研究试图促进对偏头痛病理生理学的理解，特别是可能在促进女性与月经周期相关的偏头痛发作方面发挥作用的机制。与公共卫生相关：偏头痛在女性中的患病率是女性的三倍，在大约一半的女性偏头痛患者中，头痛的频率和严重程度在月经前后增加，月经期间是与雌激素停用相关的荷尔蒙阶段。该项目将通过检测雌激素停用对大鼠偏头痛的神经元和行为相关的影响，来研究月经期偏头痛的潜在机制。这项研究将进一步研究雌激素停用效果的一个潜在机制可能与其对硬脑膜肥大细胞的影响有关。

Description (provided by applicant): Migraine affects predominantly females in their fertile years, and in close to half of all women migraineurs, the frequency and severity of migraine attacks increase around the time of menstruation. Although the mechanisms underlying these menstrually-related migraines are unclear, the abrupt decline in plasma estrogen levels during the premenstrual phase is now believed to be a critical factor. How estrogen withdrawal promotes menstrual migraine remains nevertheless speculative. Based on preliminary experiments in female rats, we hypothesized that changes in the level of reproductive hormones exert a modulatory influence on the activity of meningeal nociceptors and specifically, that estrogen withdrawal produces an increase in meningeal nociceptor sensitivity to migraine triggers such as glyceryl trinitrate (GTN). We further hypothesized that this enhancement in meningeal nociceptor activity subsequently facilitates the development of delayed pericranial hypersensitivity (a condition associated with migraine pain). Finally, we postulated that one possible mechanism underlying this pro-nociceptive effect of estrogen withdrawal may be related to the influence it exerts on dural MCs, which in turn can promote meningeal nociceptor activation. We propose to test our working hypotheses using in-vivo electrophysiological recordings as well as behavioral and histological techniques. Three specific aims are proposed: Aim 1 is to determine whether estrogen withdrawal, either occurring naturally during the estrous cycle or induced experimentally in ovariectomized (OVX) animals modulates the responses of meningeal nociceptors to infusion of the migraine-triggering molecule GTN. Aim 2 is to examine whether the enhancing effect of estrogen withdrawal on GTN-evoked activation of meningeal nociceptors is manifested behaviorally as pericranial tactile hypersensitivity. Aim 3a is to examine the relative contribution of MCs in mediating the effect of estrogen withdrawal on GTN-evoked meningeal nociceptor activation and pericranial hypersensitivity using treatments that either deplete MCs or block their degranulation. Aim 3b is to explore the possibility that one mechanism by which estrogen withdrawal enhances the effect of GTN is by affecting the propensity of dural MCs to become degranulated in response to GTN. Taken together these novel studies seek to advance the understanding of the pathophysiology of migraine and in particular, mechanisms that may play a role in promoting migraine attacks associated with the menstrual cycle in females. PUBLIC HEALTH RELEVANCE: Migraine is three times more prevalent in women, and in about half of all women migraineurs, headache frequency and severity increase around the time of menstruation, a hormonal phase associated with estrogen withdrawal. The project will study a potential mechanism underlying menstrual migraine by examining the effect of estrogen withdrawal on neuronal and behavioral correlates of migraine pain in rats. The study will further examine the possibility that one mechanism underlying the effect of estrogen withdrawal may be related to its influence on dural mast cells.