CGRP-induced light aversion in a preclinical migraine model

描述(申请人提供)：偏头痛是一种衰弱的神经系统疾病，涉及神经肽降钙素基因相关肽(CGRP)。该项目的总体目标是确定CGRP触发畏光的机制，这是偏头痛的一种常见症状。恐光症是对通常不痛苦的光线水平做出的痛苦反应。用于这些研究的一个有用的工具是Nestin/hRAMP1转基因小鼠，它对CGRP的作用敏感。这些小鼠的神经系统中CGRP受体的一个亚单位，称为人类受体活性修改蛋白1(HRAMP1)的表达增加。Nestin/hRAMP1小鼠对至少两种感觉刺激的反应增强：触摸和光。避光表型类似于畏光，中枢应用CGRP可大大增强这种表型。在化学诱导的肥大细胞脱颗粒和温和的应激范式之后，小鼠也表现出增强的避光行为。应激是偏头痛最常见的诱因之一，也会导致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，炎症信号可能会加剧这种疾病：硬脑膜肥大细胞激活三叉神经伤害性通路，肥大细胞脱颗粒触发偏头痛，消炎药通常用于偏头痛。我们假设CGRP可以作用于丘脑，在应激诱导的神经源性炎症后触发避光。这一假说是基于最近的一项发现，即丘脑后部神经元对硬脑膜和光刺激都很敏感。此外，CGRP还可激活硬脑膜肥大细胞、三叉神经细胞和丘脑后叶神经元。因此，应激诱导的肥大细胞激活有一条CGRP依赖的途径，使丘脑神经元对光敏感，导致畏光。第一个目标将确定肥大细胞在避光行为中的作用。我们将比较Nestin/hRAMP1和对照组小鼠对化学激活剂和温和应激范式的反光反应。第二个目标将确定后丘脑是否是降钙素基因相关肽和肥大细胞诱导的光厌恶的中枢神经系统靶点。将使用互补的药理和遗传策略。这些目标将为在动物模型中应激引发类似偏头痛的症状的机制提供洞察力。显然，除了降钙素基因相关肽外，还有许多基因与偏头痛有关。因此，基于hRAMP1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。拟议的研究的意义在于它们的翻译潜力，这一点在偏头痛的流行中得到了强调，几乎每5名妇女中就有1人受到影响。尽管在过去的十年里，我们对偏头痛的了解取得了进展，但许多问题仍然没有得到回答，部分原因是缺乏合适的动物模型。为了解决这些问题，我们组建了一个跨学科的团队，拥有CGRP、偏头痛、疼痛药理学和老鼠行为方面的专业知识。这项提议的影响将是一个经过验证的临床前模型，用于转化性研究，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.