Physiology of ATP Release in Chronic Pain

慢性疼痛中 ATP 释放的生理学

• 批准号: 6623258
• 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
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623258
• 关键词: adenosine triphosphate; afferent nerve; basal ganglia; chronic pain; electrophysiology; inflammation; laboratory rat; luciferin; nerve injury; neuropathology; neurophysiology; nociceptors; polyneuritis; purinergic receptor; sciatic nerve; sensory mechanism; single cell analysis; spinal ganglion; thermography; voltage /patch clamp

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：（由申请人提供）慢性炎性和神经性疼痛 是一个与临床相当相关的问题。了解机制 慢性疼痛的潜在发展和维持将是一个重要的步骤 对这种疼痛状况的合理治疗大量证据链接 神经病性慢性疼痛，伴有兴奋性增加和异常 感觉神经节内初级传入神经元中的信号产生。 化学介导的感觉神经节神经元之间的交叉兴奋， 被认为是异常放电的一种主要机制， 产生于病理性疼痛状态。然而，化学品的身份 交叉激发介质未知。三磷酸腺苷（ATP）是 在神经元激活后在感觉神经节内释放， 激活感觉神经元胞体上的受体。总的目标是 一个提议是直接检验ATP是化学介质的假设 的交叉兴奋，并确定如何释放ATP的变化， 疼痛状态。具体目标是：（1）确定被释放者的参与程度 ATP在感觉神经节内神经元交叉兴奋中的作用，2）决定 外周炎症后基础和刺激诱发的ATP释放的变化， 3)确定诱导后基础和诱发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DRG神经元。周围神经诱发交叉去极化 刺激将在来自神经元的细胞内记录期间测量， 背根神经节（DRG）。感觉神经元上的ATP受体将被操纵 通过应用选择性激动剂和拮抗剂来影响诱发的 交叉去极化ATP释放将通过荧光素酶测定。 DRG灌注液中的测定。从急性分离的DRG神经元释放的ATP将是 使用探测器贴片测量。这些研究将首先在 正常条件下，然后与a）诱导后获得的结果进行比较 外周炎症，和B）大鼠的外周神经病变。所获取的 知识可能导致开发针对异常的新疗法， 感觉神经元的兴奋性变化。