The Role of ASICs in Migraine Pathophysiology

描述(申请人提供)：偏头痛曾经被认为主要是由血管引起的，但现在越来越多地认识到它的发生和发展也涉及神经系统的不适应变化。偏头痛是最常见的神经系统疾病，高达33%的女性和13%的男性在生活中的某个阶段受到影响。尽管它广泛流行，但导致偏头痛的病理生理学仍然知之甚少，药物治疗只对大约50%的偏头痛患者有效。开发比现有疗法更有效的新疗法是有限的，部分原因是缺乏新的治疗靶点。因此，识别有助于偏头痛病理生理学的新靶点对于更有效的偏头痛治疗是至关重要的。先前的临床前研究发现，支配脑膜(即硬脑膜)的三叉神经痛感受器对肥大细胞释放的物质敏感。在压力和雌激素水平升高后，肥大细胞可以被激活，这两者都与人类的偏头痛有关。然而，肥大细胞诱导信号传递的细胞机制尚不清楚。这一假设认为，肥大细胞脱颗粒后硬脑膜细胞外pH的降低导致硬脑膜传入细胞通过开放酸敏感离子通道(ASICs)而激活。实验室最近的研究发现，已识别的硬脑膜传入细胞对由ASICs产生的电流在pH值小幅下降时做出反应。在暴露于肥大细胞介质后，这些微小的pH下降导致动作电位的激发。初步研究还表明，将降低的pH溶液直接应用于清醒动物的硬脑膜，会引发被认为与偏头痛有关的行为。这项拟议的研究将通过解决以下问题来探索ASIC介导的硬脑膜传入兴奋性和偏头痛相关疼痛行为对pH下降的反应。肥大细胞介体是否增加了硬脑膜传入的ASIC电流和pH诱导的兴奋性，这些因素是否会在pH小幅下降后导致传入活动的增强？激活硬脑膜内神经末梢上的ASIC通道是否产生传入信号的迹象，以及哪些ASIC蛋白在硬脑膜传入终末表达？肥大细胞介体是否增加了硬脑膜内ASICs激活引起的偏头痛相关行为？这项建议的目的是确定ASIC在硬脑膜内感觉终末中的作用，以及这些通道可能如何参与传入信号和偏头痛。如果ASIC被发现在偏头痛的病理生理学中发挥重要作用，这一发现将为偏头痛的药物治疗确定新的靶点，并可能导致比现有疗法更有效的新疗法。开发针对ASICs的药物最终可能会缓解目前现有疗法无法充分治疗的大量偏头痛患者。

DESCRIPTION (provided by applicant): Migraine headache was once thought to be predominately of vascular origin but it is now increasingly appreciated that its genesis and progression also involves maladaptive changes in the nervous system. Migraine represents the most common neurological disorder affecting up to 33% of women and 13% of men at some point in their lives. Despite its widespread prevalence, the pathophysiology that leads to migraine headache is still poorly understood and pharmacological treatment is only effective in about 50% of migraine sufferers. Developing new treatments with greater efficacy than those currently available is limited, in part, by a lack of new therapeutic targets. Thus, the identification of new targets that contribute to the pathophysiology of migraine headache is of critical importance for more effective migraine therapies. Prior preclinical work has found that trigeminal pain-sensing neurons (nociceptors) innervating the cranial meninges (i.e. the dura mater) are sensitive to substances released from mast cells. Mast cells can be activated following stress and increased estrogen levels, both of which are associated with migraines in humans. However, the cellular mechanisms by which mast-cell induced signaling is initiated are unknown. The hypothesis of this proposal is that decreased extracellular pH within the dura following mast-cell degranulation leads to activation of dural afferents via the opening of acid-sensing ion channels (ASICs). Recent studies in the laboratory have found that identified dural afferents respond to small drops in pH with currents generated by ASICs. Following exposure to mast cell mediators, these small pH drops lead to firing of action potentials. Preliminary studies also show that direct application of decreased pH solutions to the dura mater of awake animals elicit behaviors thought to be relevant to migraine pain. The proposed studies will explore ASIC-mediated dural afferent excitability and migraine-related pain behaviors in response to drops in pH by addressing the following questions. Are ASIC currents and pH-induced excitability of dural afferents increased by mast cell mediators and do these factors lead to enhanced afferent activity following small drops in pH? Does activation of ASIC channels on neuronal endings within the dura produce signs of afferent signaling and which ASIC proteins are expressed on dural afferent endings? Do mast-cell mediators increase the migraine-related behavior induced by activation of ASICs within the dura? The goal of this proposal is to determine the role of ASICs on sensory endings within the dura and how these channels might contribute to afferent signaling and migraine headache. If ASICs are found to play an important role in migraine pathophysiology, this finding would identify new targets for the pharmacological treatment of migraine and could lead to new therapies with increased efficacy over those currently available. Developing drugs targeting ASICs may ultimately provide relief to the large numbers of migraine patients that are not being adequately treated by currently available therapies.