The Role of ASICs in Migraine Pathophysiology

ASIC 在偏头痛病理生理学中的作用

• 批准号: 8185578
• 负责人: GREGORY O DUSSOR
• 金额: $ 32.01万
• 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/8185578
• 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. PUBLIC HEALTH RELEVANCE: Migraine headache is the most common neurological condition but a substantial percentage of migraine sufferers are not adequately treated by currently available therapeutics. Development of new treatments is limited, in part, by a lack of understanding of the mechanisms contributing to this disorder. The goal of this proposal is to investigate the role of novel targets in migraine pathophysiology (acid-sensing ion channels) that may provide new therapeutic opportunities for the treatment of migraine headache.

描述（由申请人提供）：曾经认为偏头痛的头痛主要是血管起源的，但现在越来越多地赞赏其起源和进展也涉及神经系统的适应不良变化。偏头痛代表了最常见的神经系统疾病，其中一生中某个时候影响了33％的女性和13％的男性。尽管普遍存在，但导致偏头痛的病理生理学仍然很少了解，药理治疗仅在约50％的偏头痛患者中有效。与当前可用的疗效相比，开发具有更大疗效的新治疗方法在某种程度上是由于缺乏新的治疗靶标而受到限制。因此，鉴定有助于偏头痛的病理生理学的新靶标对于更有效的偏头痛疗法至关重要。先前的临床前工作发现，支配颅脑介质（即硬脑膜）的三叉神经疼痛神经元（伤害感受器）对从肥大细胞中释放的物质敏感。肥大细胞可以在压力和雌激素水平升高后激活，这两者都与人类的偏头痛有关。但是，启动肥大细胞诱导信号传导的细胞机制尚不清楚。该提案的假设是，桅杆脱粒后，在硬脑膜内的细胞外pH值降低会导致通过开放酸性离子通道（ASIC）激活硬脑膜传入。实验室的最新研究发现，鉴定出的硬脑膜传入对ASIC产生的电流的pH值小滴剂反应。暴露于肥大细胞介质后，这些小的pH下降导致动作电位发射。初步研究还表明，将pH溶液降低到清醒动物的硬脑膜上的直接应用引起的行为被认为与偏头痛有关。拟议的研究将通过解决以下问题来探讨ASIC介导的硬膜传入兴奋性和与偏头痛相关的疼痛行为，以响应pH下降。肥大细胞介质的ASIC电流和pH诱导的硬膜传入量是否增加了，这些因素是否会导致pH下少量下降后的传入活动增强？硬脑膜内神经元末端的ASIC通道的激活会产生传入信号的迹象，以及哪些ASIC蛋白在硬脑膜传入末端表达？桅杆细胞介体是否会增加硬脑膜内ASIC引起的偏头痛相关行为？该提案的目的是确定ASIC在硬脑膜内感官末端的作用，以及这些渠道如何导致传入的信号传导和偏头痛。如果发现ASIC在偏头痛的病理生理学中起重要作用，这一发现将确定偏头痛药理治疗的新靶标，并可能导致新的疗法，对目前可用的疗法提高了疗效。开发针对ASIC的药物最终可能会缓解许多偏头痛患者，而这些患者尚未得到当前可用的疗法的充分治疗。 公共卫生相关性：偏头痛是最常见的神经系统疾病，但偏头痛患者的很大一部分没有得到当前可用的治疗剂的充分治疗。新疗法的发展部分是有限的，部分原因是对导致这种疾病的机制缺乏理解。该提案的目的是研究新靶标在偏头痛病理生理学（酸性离子通道）中的作用，该病因可能为治疗偏头痛的治疗提供新的治疗机会。