Mechanisms of pain modulation by the migraine drug sumatriptan

描述(由申请人提供)：偏头痛是一种流行的致残性疾病，继续困扰着最好的现有药物治疗。新的更有效的治疗方法的一个重要障碍是我们缺乏对相关神经生物学靶点的关键洞察力。这是因为导致这种疾病的基本机制仍然难以捉摸，而偏头痛的病理生理学的主流理论是基于间接的或相互矛盾的证据。鉴于几乎没有直接证据支持我们对偏头痛的理解，任何对舒马曲坦在大脑中关键的抗偏头痛作用的根本洞察将对我们理解这种疾病和合理设计新的治疗方法具有重要意义。该项目的总体目标是阐明偏头痛特效药舒马曲坦的神经生物学作用。舒马曲坦在外周对神经源性炎症和感觉神经元的抑制作用已被很好地描述，但舒马曲坦在大脑中的作用机制实际上仍未被探索。该项目重点研究舒马曲坦对杏仁核内疼痛相关回路的作用，以及它通过激活5HT1D受体对疼痛的情感-情绪处理的影响。重要的是，由于偏头痛的一个主要临床特征是所有感觉方式的情感成分的干扰，舒马曲坦对杏仁核内疼痛的情感-情绪处理的调节可能是舒马曲坦抗偏头痛活动的关键部位，并可能成为未来偏头痛治疗的重要靶点。这位K02独立科学家职业发展奖的申请者是一位长期致力于神经科学研究事业的内科科学家。这一K02奖项将支持他继续职业发展和研究，这将导致获得同行审查的独立调查人员发起的资金。 公共卫生相关性：偏头痛是一种常见的致残性神经疾病，其治疗不足是痛苦、残疾和精神共病的主要来源。尽管接受了最好的治疗，许多美国人仍然患有偏头痛，在美国，偏头痛仍然是导致残疾和生产力丧失的最常见的神经原因。本项目旨在了解最重要的偏头痛专用处方药舒马曲坦的作用机制，利用解剖学、分子和行为学方法了解其疼痛调节作用，希望它将产生重要的见解，从而导致新的更有效的治疗。

DESCRIPTION (provided by applicant): Migraine is a prevalent and disabling disorder that continues to confound best available medical therapy. An important obstacle to new more effective therapy is that we lack critical insights as to the relevant neurobiological targets. This is because the basic mechanisms contributing to this disorder remain elusive, and prevailing theories of the pathophysiology of migraine are based upon indirect or conflicting lines of evidence. Given what little direct evidence supports our understanding of migraine, any fundamental insight into the critical anti-migraine actions of sumatriptan action in the brain would be of great significance to our understanding of the disorder and the rational design of new therapies. The overall goal of this project is to elucidate the neurobiological actions of the migraine-specific drug sumatriptan. The inhibitory actions of sumatriptan in the periphery, on neurogenic inflammation and sensory neurons, are well described, but the mechanisms of sumatriptan in the brain remain virtually unexplored. This project focuses on the action of sumatriptan on pain-related circuits within the amygdala, and its influence on the affective-emotional processing of pain, through the activation of the 5HT1D receptor. Importantly, because a central clinical feature of migraine is the disturbance of the affective component of all sensory modalities, the modulation of the affective-emotional processing of pain by sumatriptan within the amygdala could potentially be a critical site for the anti-migraine activity of sumatriptan, and could be an important target for migraine therapy in the future. This applicant for a K02 Independent Scientist Career Development Award is a physician scientist with a longstanding commitment to a career in neuroscience research. This K02 award will support his continued career development and research that will lead to obtaining peer-reviewed, independent investigator-initiated funding. PUBLIC HEALTH RELEVANCE: Migraine is a common and disabling neurological disorder whose under-treatment is a major source of suffering, disability, and psychiatric comorbidity. Many Americans continue to suffer from migraine despite best medical treatment, and it remains the single most common neurological cause of disability and lost productivity in the United States. This project seeks to understand the mechanism of action of the foremost class of prescribed migraine-specific medication, sumatriptan, utilizing anatomical, molecular, and behavioral approaches to understanding its pain-modulatory actions, in hopes that it will yield important insights that will lead to new more effective therapy.