The Role of ASICs in Migraine Pathophysiology

ASIC 在偏头痛病理生理学中的作用

• 批准号: 8296514
• 负责人: GREGORY O DUSSOR
• 金额: $ 32.64万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296514
• 关键词: ASIC channel; Action Potentials; Address; Affect; Animal Model; Animals; Behavior; Blood Vessels; Calcitonin Gene-Related Peptide; Cell Degranulation; Cephalic; Development; Disease; Drops; Drug Delivery Systems; Dura Mater; Electrophysiology (science); Environment; Epoprostenol; Estrogens; Event; Exploratory Behavior; Exposure to; Face; Functional disorder; Goals; Headache; Histamine; Human; Hypersensitivity; In Vitro; Infusion procedures; Ion Channel Protein; Laboratories; Lead; Link; Mediating; Mediator of activation protein; Membrane; Meningeal; Meninges; Migraine; Nervous system structure; Neurologic; Neurons; Nitroglycerin; Nociceptors; Pain; Patients; Pharmacological Treatment; Play; Prevalence; Research; Role; Sensory; Serotonin; Signal Transduction; Solutions; Stabilizing Agents; Stress; Testing; Therapeutic; Trigeminal Neuralgia; Tryptase; Woman; Work; allodynia; awake; direct application; extracellular; in vivo; mast cell; men; nervous system disorder; new therapeutic target; novel; novel therapeutics; pain behavior; patch clamp; pre-clinical; response

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.

描述（由申请人提供）：偏头痛曾被认为主要是血管源性的，但现在越来越多地认识到其发生和进展也涉及神经系统的适应不良变化。偏头痛是最常见的神经系统疾病，在生命的某个阶段影响多达33%的女性和13%的男性。尽管其广泛流行，导致偏头痛的病理生理学仍然知之甚少，药物治疗仅对约50%的偏头痛患者有效。开发比现有治疗方法更有效的新治疗方法受到限制，部分原因是缺乏新的治疗靶点。因此，鉴定有助于偏头痛的病理生理学的新靶点对于更有效的偏头痛治疗至关重要。先前的临床前工作已经发现，支配脑膜（即硬脑膜）的三叉神经疼痛感测神经元（伤害感受器）对肥大细胞释放的物质敏感。肥大细胞可以在压力和雌激素水平增加后被激活，这两者都与人类偏头痛有关。然而，肥大细胞诱导的信号传导启动的细胞机制尚不清楚。该建议的假设是，肥大细胞脱粒后硬脑膜内细胞外pH值降低，导致通过开放酸敏感离子通道（ASIC）激活硬脑膜传入。最近的实验室研究发现，已识别的硬膜传入神经对pH值的小幅下降产生响应，电流由ASIC产生。暴露于肥大细胞介质后，这些小的pH值下降导致动作电位的激发。初步研究还表明，直接将pH值降低的溶液应用于清醒动物的硬脑膜会引起被认为与偏头痛相关的行为。拟议的研究将探讨ASIC介导的硬脑膜传入兴奋性和偏头痛相关的疼痛行为，以应对pH值下降，解决以下问题。ASIC电流和pH诱导的硬膜传入兴奋性是否由肥大细胞介质增加，这些因素是否导致pH小幅下降后传入活动增强？在硬脑膜内的神经元末梢上的ASIC通道的激活是否产生传入信号的迹象以及在硬脑膜传入末梢上表达哪些ASIC蛋白？肥大细胞介导物是否增加硬脑膜内ASIC激活诱导的偏头痛相关行为？这项研究的目的是确定ASIC在硬脑膜内感觉末梢上的作用，以及这些通道如何有助于传入信号和偏头痛。如果发现ASIC在偏头痛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，并可能导致新的治疗方法，其疗效高于目前可用的治疗方法。开发针对ASIC的药物可能最终会缓解目前可用疗法无法充分治疗的大量偏头痛患者。