Mechanisms of pain modulation by the migraine drug sumatriptan

描述（由申请人提供）：偏头痛是一种普遍的致残疾病，一直困扰着现有的最佳医学治疗。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认识。这是因为导致这种疾病的基本机制仍然难以捉摸，偏头痛的病理生理学的主流理论是基于间接或相互矛盾的证据线。考虑到支持我们对偏头痛的理解的直接证据很少，任何关于舒马匹坦在大脑中作用的关键抗偏头痛作用的基本见解都将对我们对这种疾病的理解和新疗法的合理设计具有重要意义。该项目的总体目标是阐明偏头痛特异性药物舒马曲坦的神经生物学作用。舒马匹坦在外周的抑制作用，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，但舒马匹坦在大脑中的机制仍未被探索。本项目主要研究舒马曲坦对杏仁核内疼痛相关回路的作用，以及通过激活5HT1D受体对疼痛的情感-情绪加工的影响。重要的是，由于偏头痛的一个中心临床特征是所有感觉模式的情感成分的干扰，在杏仁核中调节疼痛的情感-情绪处理可能是舒马曲坦抗偏头痛活性的关键部位，并且可能是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人是一位长期致力于神经科学研究的内科科学家。该K02奖将支持他的持续职业发展和研究，这将导致获得同行评审，独立的研究者发起的资金。

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.