CGRP-induced light aversion in a preclinical migraine model

临床前偏头痛模型中 CGRP 诱导的光厌恶

• 批准号: 8268972
• 负责人: Andrew F Russo
• 金额: $ 41.37万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268972
• 关键词: A Mouse; Acute; Address; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Behavior; Biological; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cell Degranulation; Chemicals; Clinical Trials; Complex; Couples; Development; Disease; Drug Delivery Systems; Exhibits; Feedback; Future; Gene Expression; Genes; Genetic; Headache; Human; Hypersensitivity; Inflammation; Inflammatory; Lead; Light; Link; Measurable; Mediating; Migraine; Mind; Modeling; Mus; Nervous system structure; Neurogenic Inflammation; Neurologic; Neurons; Neuropeptides; Nociception; Pain; Painless; Pathway interactions; Peptide Synthesis; Pharmaceutical Preparations; Pharmacology; Phenotype; Photophobia; Physiological; Pre-Clinical Model; Prevalence; Regulation; Rodent; Role; Sensory; Signal Pathway; Signal Transduction; Site; Societies; Stress; Symptoms; Synapsins; System; Testing; Thalamic structure; Touch sensation; Transgenes; Transgenic Mice; Transgenic Organisms; Trigeminal Nuclei; Trigeminal System; Viral Vector; Woman; acute stress; base; gene function; innovation; insight; mast cell; mouse model; nervous system disorder; nestin protein; new therapeutic target; novel therapeutics; pain behavior; pre-clinical; receptor-activity-modifying protein; recombinase; relating to nervous system; research study; response; sensory stimulus; stressor; tool; translational study

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.

描述（由申请人提供）：偏头痛是一种使神经肽基因相关肽（CGRP）的神经系统衰弱的神经系统疾病。该项目的总体目的是确定CGRP触发恐惧症的机制，这是偏头痛的常见症状。恐惧症是对通常非抚摸光水平的痛苦反应。这些研究的有用工具是Nestin/Hramp1转基因小鼠，该小鼠对CGRP作用敏感。小鼠的神经系统表达升高了称为人体受体活性修饰蛋白1（HRAMP1）的CGRP受体亚基的表达。 Nestin/Hramp1小鼠对至少两个感觉刺激的反应增强：触摸和光。光厌恶表型类似于恐惧恐惧症，并且通过CGRP的中央给药可大大增强。在化学诱导的肥大细胞脱粒和轻度应激范式后，小鼠还显示出增强的光厌恶行为。压力是偏头痛最常见的触发因素之一，也引起硬脑膜肥大细胞的脱粒。有证据表明，偏头痛是一种神经疾病，可能会因炎症信号而加剧：硬脑膜肥大细胞激活三叉神经伤害性途径，肥大细胞脱粒会触发偏头痛的头痛，抗炎药通常用于偏头痛。我们假设CGRP可以在丘脑中作用，以引发压力引起的神经源性炎症后的光厌恶。该假设是基于最近的发现，即丘脑后神经元对硬脑膜和光刺激均敏感。此外，CGRP可以激活硬膜肥大细胞，三叉神经元和后丘脑神经元。因此，有一个依赖CGRP的途径，用于应力诱导的肥大细胞活化，以使丘脑神经元对光敏感，从而导致恐惧症。第一个目标将在光厌恶行为中确定肥大细胞的贡献。响应化学激活剂和轻度应激范式的光厌恶将在Nestin/Hramp1和对照小鼠之间进行比较。第二个目标将确定丘脑后丘脑是否是CGRP和肥大细胞诱导的光厌恶的中枢神经系统靶标。将使用补充药理学和遗传策略。这些目的将提供有关压力在动物模型中引发类似偏头痛的症状的机制的见解。显然，除CGRP外，偏头痛还将涉及许多基因。因此，基于HRAMP1的策略使用定义的小鼠系统的优势为复杂疾病的研究提供了一种创新的方法。拟议的研究的意义在于它们的翻译潜力，这是由于偏头痛的患病率强调，每5名妇女中几乎有1个。尽管在过去十年中，我们对偏头痛的理解取得了进步，但许多问题仍未得到答案，部分原因是不足于适当的动物模型。为了解决这些问题，我们组建了一个跨学科团队，具有CGRP，偏头痛，疼痛药理学和老鼠行为的专业知识。该提案的影响将是转化研究的经过验证的临床前模型，以开发偏头痛的新疗法。