CGRP-induced light aversion in a preclinical migraine model

描述（由申请方提供）：偏头痛是一种涉及神经肽降钙素基因相关肽（CGRP）的衰弱性神经系统疾病。该项目的总体目标是确定CGRP触发偏头痛的一种常见症状--头痛恐惧症的机制。畏光症是一种对通常无痛苦的光线水平的痛苦反应。这些研究的一个有用的工具是巢蛋白/hRAMP 1转基因小鼠，这是敏感的CGRP行动。小鼠神经系统中CGRP受体亚基的表达水平升高，该亚基被称为人类受体活性修饰蛋白1（hRAMP 1）。Nestin/hRAMP 1小鼠对至少两种感官刺激的反应增强：触摸和光。光厌恶表型类似于恐光症，并且通过CGRP的中枢给药而大大增强。小鼠在化学诱导的肥大细胞脱颗粒和轻度应激范例后也显示出增强的光厌恶行为。压力是偏头痛最常见的诱因之一，也会引起硬脑膜肥大细胞脱颗粒。有证据表明，偏头痛是一种神经疾病，可以通过炎症信号加剧：硬脑膜肥大细胞激活三叉神经伤害性通路，肥大细胞脱粒触发偏头痛样头痛，抗炎药物通常用于偏头痛。我们假设CGRP可以在丘脑中起作用，从而在应激诱导的神经源性炎症后触发光厌恶。这一假设是基于最近的一项发现，即后丘脑神经元对硬脑膜和光刺激都敏感。此外，CGRP可以激活硬脑膜肥大细胞、三叉神经元和后丘脑神经元。因此，存在CGRP依赖性途径，用于应激诱导的肥大细胞活化以使丘脑神经元对光敏感，从而导致恐光症。第一个目标是确定肥大细胞在光厌恶行为中的作用。将在巢蛋白/hRAMP 1和对照小鼠之间比较响应于化学活化剂和轻度应激范例的光厌恶。第二个目标将确定后丘脑是否是CGRP和肥大细胞诱导的光厌恶的CNS靶点。将使用补充的药理学和遗传学策略。这些目标将为压力在动物模型中引发偏头痛样症状的机制提供见解。显然，除了CGRP之外，许多基因也会参与偏头痛。因此，基于hRAMP 1的策略提供了一种创新的方法，利用定义的小鼠系统的优势来研究复杂的疾病。拟议研究的意义在于其转化潜力，偏头痛的患病率强调了这一点，几乎每5名女性中就有1名受到影响。尽管在过去的十年中，我们对偏头痛的理解取得了进展，但许多问题仍然没有答案，部分原因是缺乏适当的动物模型。为了解决这些问题，我们组建了一个跨学科团队，他们在CGRP，偏头痛，疼痛药理学和小鼠行为方面具有专业知识。该提案的影响将是转化研究的有效临床前模型，以开发偏头痛的新疗法。

DESCRIPTION (provided by applicant): Migraine is a debilitating neurological condition involving the neuropeptide calcitonin gene-related peptide (CGRP). The overall objective of this project is to identify mechanisms by which CGRP triggers photophobia, a common symptom of migraine. Photophobia is a painful response to ordinarily non-painful levels of light. A useful tool for these studies is the nestin/hRAMP1 transgenic mouse, which is sensitized to CGRP actions. The mice have elevated nervous system expression of a subunit of the CGRP receptor called human receptor activity-modifying protein 1 (hRAMP1). Nestin/hRAMP1 mice have heightened responses to at least two sensory stimuli: touch and light. The light aversive phenotype is analogous to photophobia and is greatly enhanced by central administration of CGRP. The mice also display enhanced light aversive behavior following chemically induced mast cell degranulation and a mild stress paradigm. Stress is one of the most common triggers of migraine and also induces dural mast cell degranulation. There is evidence that migraine is a neural disorder that can be exacerbated by inflammatory signals: dural mast cells activate trigeminal nociceptive pathways, mast cell degranulation triggers migraine-like headaches, and anti-inflammatory drugs are commonly used for migraine. We hypothesize that CGRP can act in the thalamus to trigger light aversion following stress-induced neurogenic inflammation. This hypothesis is based on a recent finding that posterior thalamic neurons are sensitive to both dural and light stimulation. Furthermore, CGRP can activate dural mast cells, trigeminal neurons, and posterior thalamic neurons. Thus, there is a CGRP-dependent pathway for stress-induced mast cell activation to sensitize thalamic neurons to light, leading to photophobia. The first aim will establish the contribution of mast cells in light aversive behavior. Light aversion in response to a chemical activator and a mild stress paradigm will be compared between nestin/hRAMP1 and control mice. The second aim will identify whether the posterior thalamus is a CNS target of CGRP- and mast cell-induced light aversion. Complementary pharmacological and genetic strategies will be used. These aims will provide insight to the mechanisms by which stress can trigger a migraine-like symptom in an animal model. Clearly, a host of genes will be involved in migraine in addition to CGRP. Hence, the hRAMP1-based strategy provides an innovative approach using the advantages of a defined mouse system for the study of complex diseases. The significance of the proposed studies is their translational potential, which is underscored by the prevalence of migraine, affecting almost 1 in every 5 women. Despite advances in our understanding of migraine over the past decade, many questions remain unanswered, in part due to the paucity of appropriate animal models. To address these issues, we have assembled an interdisciplinary team with expertise in CGRP, migraine, pain pharmacology, and mouse behavior. The impact of this proposal will be a validated preclinical model for translational studies to develop new therapeutics for migraine.