Mitochondrial regulation of nociceptor function

慢性疼痛每年影响超过5000万美国人，导致非常严重的疾病。 个人和社会成本。更让人进退两难的是， 止痛药在过去十年里几乎翻了两番。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不同， 疼痛，因此，深入了解分子和细胞机制的基础上， 向慢性疼痛的转变是改善和扩大治疗选择的根本。 痛觉过敏启动是一个令人信服的模型过渡到慢性疼痛，其中最初的 伤害解决，但使动物处于第二次伤害诱导的启动状态， 极大地延长了疼痛反应。这里提出的实验将检查的影响， 线粒体动力学对急性和慢性炎性疼痛发展的比较 神经病理性疼痛的神经损伤模型，并将探讨介导 提出的内源性解偶联机制和线粒体的抗伤害作用 解偶联药物具体目标1将研究线粒体功能如何在 伤害性损伤的反应以及线粒体调节对急性痛觉过敏的影响 感觉神经节Specific Aim 2将使用膜片钳电生理学来证明变化 在感觉神经元响应于线粒体功能操纵的电特性中， 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， 过渡到慢性疼痛，并将阐明细胞信号通路调节的影响， 线粒体功能的炎症和神经病理性疼痛慢性化。这项建议会 使用创新的方法来探索新的机制，线粒体影响 急性和慢性疼痛的表现，并测试针对这些治疗潜力 缓解疼痛的机制。

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.