Mitochondrial regulation of nociceptor function

慢性疼痛每年影响5000多万美国人，导致非同寻常的 个人和社会成本。雪上加霜的是，与处方阿片类药物有关的死亡 在过去的十年里，止痛药几乎翻了两番。疼痛的临床挑战 有证据表明，慢性疼痛与急性疼痛在机制上是不同的，这一点强调了管理。 因此，对疼痛的分子和细胞机制有深入的了解 向慢性疼痛的过渡是改善和扩大治疗选择的基础。 痛觉过敏启动是一种令人信服的向慢性疼痛过渡的模型，在这种模型中，最初的 受伤会痊愈，但会让动物处于一种预备状态，在这种状态下，第二次侮辱会导致 大大延长了疼痛反应时间。这里提出的实验将检验 线粒体动力学在急性和慢性炎症性疼痛发生中的比较 建立神经病理性疼痛的神经损伤模型，并将探讨其分子机制 内源性解偶联机制和线粒体抗伤害性作用的研究进展 去偶联药物。特殊目标1将研究线粒体功能是如何变化的 大鼠对伤害性伤害的反应及线粒体调节对急性痛敏的影响 感觉神经节。特殊目标2将使用膜片钳电生理学来演示变化 在感觉神经元对线粒体功能的操纵作出反应的电特性中， 并将确定介导线粒体对神经元影响的细胞信号通路 兴奋性。具体目标3将描述线粒体功能的变化，这些变化是 转化为慢性疼痛，并将阐明细胞信号通路对 线粒体在炎症和神经病理性疼痛时代化中的作用。这项提议将 使用创新的方法来探索线粒体影响细胞周期的新机制 急性和慢性疼痛的表现，并测试针对这些的治疗潜力 止痛机制。

Chronic pain affects more than 50 million Americans per year, resulting in extraordinary personal and societal costs. Adding to the dilemma, deaths involving prescription opiate analgesics have almost quadrupled in the last ten years. The clinical challenge of pain management is underscored by evidence that chronic pain is mechanistically distinct from acute pain, therefore a thorough understanding of the molecular and cellular mechanisms underlying the transition to chronic pain is fundamental to improving and expanding treatment options. Hyperalgesic priming is a compelling model of the transition to chronic pain in which an initial injury resolves, but leaves the animal in a primed state in which a second insult induces a greatly prolonged pain response. Experiments proposed here will examine the impact of mitochondrial dynamics on the development of acute and chronic inflammatory pain compared to a nerve injury model of neuropathic pain, and will explore molecular mechanisms mediating proposed anti-nociceptive actions of endogenous uncoupling mechanisms and mitochondrial uncoupling drugs. Specific Aim 1 will examine the how mitochondrial function changes in response to noxious insult and the impact of mitochondrial regulation on acute hyperalgesia in sensory ganglia. Specific Aim 2 will use patch clamp electrophysiology to demonstrate changes in electrical properties of sensory neurons in response to manipulation of mitochondrial function, and will identify cell signaling pathways that mediate mitochondrial effects on neuronal excitability. Specific Aim 3 will characterize changes in mitochondrial function unique to the transition to chronic pain, and will elucidate cell signaling pathways modulating the impact of mitochondrial function on inflammatory and neuropathic pain chronification. This proposal will use innovative approaches to explore novel mechanisms by which mitochondria influence the manifestation of acute and chronic pain, and test the therapeutic potential of targeting these mechanisms for pain relief.