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Physiology of ATP Release in Chronic Pain

慢性疼痛中 ATP 释放的生理学

基本信息

批准号：
6858799
负责人：
YOSHIZO MATSUKA
金额：
$ 12.42万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2008-03-31
项目状态：
已结题

项目摘要

DESCRIPTION: (provided by applicant) Chronic inflammatory and neuropathic pain is a problem of considerable clinical relevance. Understanding the mechanisms underlying development and maintenance of chronic pain would be a major step towards rational treatment of such pain conditions. Considerable evidence links chronic pain of neuropathic origin with increased excitability and abnormal signal generation in primary afferent neurons within sensory ganglia. Chemically-mediated cross-excitation between neurons in sensory ganglia has been proposed as one major mechanism by which abnormal discharges can be generated in pathological pain states. However, the identity of the chemical mediator of cross-excitation is unknown. Adenosine triphosphate (ATP) is released within sensory ganglia following neuronal activation and was shown to activate receptors on somata of sensory neurons. The overall goal of this proposal is to directly test the hypothesis that ATP is the chemical mediator of cross-excitation and to determine how release of ATP changes in pathological pain states. The specific aims are to: 1) determine the involvement of released ATP in cross-excitation of neurons within sensory ganglia, 2) determine the changes in basal and stimulus-evoked ATP release after peripheral inflammation, 3) determine the changes in basal and evoked ATP release after induction of sciatic neuropathy, 4) compare ATP release from different types of isolated and labeled DRG neurons. Cross-depolarization evoked by peripheral nerve stimulation will be measured during intracellular recordings from neurons in dorsal root ganglia (DRG). ATP receptors on sensory neurons will be manipulated by application of selective agonists and antagonists to influence evoked cross-depolarization. ATP release will be measured by the luciferin-luciferase assay in DRG perfusates. ATP release from acutely isolated DRG neurons will be measured using detector patches. These studies will be carried out first under normal conditions and then compared to results obtained after induction of a) peripheral inflammation, and b) peripheral neuropathy in rats. The acquired knowledge may lead to the development of novel therapeutics targeting abnormal excitability changes in sensory neurons.

描述：(申请人提供)慢性炎症性和神经性疼痛是一个具有相当临床意义的问题。了解相关机制慢性疼痛的潜在发展和维持将是重要的一步对这种疼痛状况进行合理的治疗。相当多的证据链接神经源性慢性疼痛，兴奋性增加，异常感觉神经节内初级传入神经元的信号产生。感觉神经节神经元之间的化学介导的交叉兴奋被认为是异常放电的一种主要机制在病理性疼痛状态下产生。然而，这种化学物质的身份交叉激发的介体未知。三磷酸腺苷(ATP)是在神经元激活后在感觉神经节内释放，并被证明激活感觉神经元胞体上的受体。这个项目的总体目标是建议是直接检验三磷酸腺苷是化学介体的假设以确定在病理情况下ATP释放是如何变化的疼痛状态。具体目标是：1)确定被释放者的参与 ATP在感觉神经节内神经元的交叉兴奋中，2)决定外周炎症后基础和刺激诱发的ATP释放的变化， 3)测定诱导后基础和诱发的ATP释放的变化坐骨神经病变，4)比较不同类型的分离和标记的背根节神经元。周围神经诱发的交叉除极刺激将在细胞内记录来自神经元的过程中测量背根节(DRG)。感觉神经元上的ATP受体将被操纵应用选择性激动剂和拮抗剂影响诱发交叉去极化。ATP的释放将通过荧光素-荧光素酶来测量背根神经节中的测定呈灌流状态。急性分离的背根节神经元的ATP释放将是使用探测器贴片进行测量。这些研究将首先在以下情况下进行正常情况下，然后与诱导后获得的结果进行比较) 外周炎症，以及b)大鼠周围神经病变。被收购的知识可能导致针对异常的新疗法的开发感觉神经元的兴奋性改变。