CGRP's effect on hearing and balance in a mouse model of migraine

偏头痛是一种严重的慢性神经系统疾病，影响全球约18%的人，其中大多数人患有偏头痛。 女性（3：1）。偏头痛的特征是使人衰弱的头痛和恶心的反复发作， 感觉敏感性增强，如光（恐光症）和声音（恐声症）。近来这个字 42%的偏头痛患者还患有平衡问题和头晕，称为 前庭性偏头痛（VM）。VM是眩晕诊所中眩晕的主要原因，估计影响1%的 总人口。临床上，曲坦类药物（5-羟色胺1B/1D受体激动剂）可以减少恐惧症 和偏头痛，但往往不能缓解其他VM症状。因此，迫切需要 验证VM的临床前模型。 神经肽降钙素基因相关肽（CGRP）被认为是偏头痛的关键因素， CGRP阻滞剂在临床试验中对头痛的疗效，注射CGRP会引发偏头痛。 我们已经开发了CGRP致敏的偏头痛转基因小鼠模型， 当CGRP被集中或全身递送时，我们已经证明CGRP 阻断剂可以阻断这些小鼠中CGRP诱导的光敏性，但是全身递送的CGRP阻断剂 不能有效地穿透CNS，并且这些阻断剂不能有效地对抗中枢诱导的 偏头痛的光敏感性涉及全身和中枢成分。 CGRP也广泛分布于整个前庭CNS，并且含有CGRP的传出纤维投射到前庭中枢神经系统。 所有的内耳器官CGRP也在前庭和听觉系统中发出信号，正如我们在一项研究中发现的那样。 不同的小鼠模型，CGRP的损失减少前庭眼反射（VOR）的增益，减少耳石， 诱发动力学降低，降低耳蜗神经中的声音诱发活动，并损害旋转杆（平衡） 性能然而，目前尚不清楚CGRP是否在VM中起中枢或外周作用;这将影响 治疗途径和疗效。我们建议测量临床VM症状的小鼠同源物，即; 声音恐惧症，不平衡，恶心和运动病易感性;并将在 三种小鼠系：i）野生型（WT）同窝对照和CGRP致敏小鼠模型，ii）神经元- 致敏的CGRP受体（nestinRAMP 1）或iii）整体致敏的CGRP受体（globalRAMP 1）。我们 假设升高的CGRP敏感性将有助于VM中发现的增加的敏感性;以及 这些VM症状将通过CGRP阻断剂得到改善。 从这些研究中获得的信息将直接评估CGRP致敏小鼠是否 已经显示出反映偏头痛恐惧症的模型也可以反映在VM中观察到的缺陷。 这种VM的临床前模型可以用于未来的转化研究，以开发和测试新的VM。 治疗学!

Migraine is a severe and chronic neurological disorder that affects ~18% of people worldwide, majority female (3:1). Migraine is characterized by recurrent attacks of debilitating headaches and nausea, with heightened sensory sensitivities, such as light (photophobia) and sound (phonophobia). Recently it has become recognized that ~42% of migraine patients also suffer from balance problems and dizziness, termed vestibular migraine (VM). VM is a major cause of vertigo in dizziness clinics, and is estimated to affect 1% of the overall population. Clinically, triptans (serotonin 5-HT 1B/1D receptor agonists) can reduce photophobia and headaches in migraine, but often do not relieve other VM symptoms. Thus, there is an urgent need for validated preclinical models for VM. The neuropeptide calcitonin gene-related peptide (CGRP) is recognized as a key player in migraine based on the efficacy of CGRP blockers in clinical trials against headache, and injection of CGRP triggers migraine. We have developed CGRP-sensitized transgenic mouse models for migraine that have heightened responses to light (photophobia) when CGRP is delivered either centrally or systemically. We have shown that CGRP blockers can block CGRP-induced photosensitivity in these mice, yet CGRP blockers delivered systemically cannot effectively penetrate the CNS, and these blockers are not effective against centrally-induced photophobia, suggesting that photosensitivity in migraine involves both systemic and central components. CGRP is also widely distributed throughout the vestibular CNS, and CGRP-containing efferent fibers project to all inner ear endorgans. CGRP is also signaling in the vestibular and auditory systems, as we discovered in a different mouse model, that the loss of CGRP reduces the vestibulo-ocular reflex (VOR) gain, reduces otolith- evoked dynamics reduces, reduces sound-evoked activity in the cochlear nerve, and impairs rotarod (balance) performance. Yet, it is not yet known if CGRP is acting centrally or peripherally in VM; which would influence treatment routes and efficacy. We propose to measure mouse homologues of clinical VM symptoms namely; phonophobia, imbalance, nausea, and motion-sickness susceptibility; and will investigate these measures in three mouse lines: i) wildtype (WT) littermate controls and CGRP-sensitized mouse models with ii) neuronally- sensitized CGRP receptors (nestinRAMP1) or iii) globally-sensitized CGRP receptors (global RAMP1). Our hypothesis is that elevated CGRP-sensitivity will contribute to increased sensitivities found in VM; and that these VM symptoms will be ameliorated by CGRP blockers. Information gained from these studies will provide a direct assessment of whether CGRP-sensitized mouse models that have been shown to mirror the photophobia of migraine, can also mirror deficits observed in VM. Such a preclinical model of VM could be used for future translational studies to develop and test new therapeutics. !