Mitochondrial regulation of nociceptor function

伤害感受器功能的线粒体调节

基本信息

批准号：
10644865
负责人：
DEREK C MOLLIVER
金额：
$ 43.73万
依托单位：
UNIVERSITY OF NEW ENGLAND
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644865
关键词：
2,4-Dinitrophenol ATP Synthesis Pathway Acute Acute Pain Acute inflammatory pain Affect Afferent Neurons American Analgesics Animals Attenuated Automobile Driving Behavioral Bioenergetics Biological Assay Buffers Cell Differentiation process Cell Line Cells Cessation of life Chronic inflammatory pain Clinical Coupled Dangerousness Data Development Diabetes Mellitus Dinitrophenols Dissociation Dose Drug Targeting Drug usage Electrophysiology (science)Female Gene Deletion Genus Hippocampus Glycolysis Human Hyperalgesia Hypersensitivity In Vitro Inflammation Inflammatory Injury Intractable Pain Measures Mechanics Mediating Membrane Potentials Messenger RNA Metabolic Mitochondria Modeling Molecular Mus Nerve Crush Neurodegenerative Disorders Neurons Neuropathy Nociceptors Opioid Analgesics Oxidative Stress Pain Pain management Pharmaceutical Preparations Phosphoproteins Physiological Pre-Clinical Model Production Property Protein Isoforms Proteins RNA Reactive Oxygen Species Receptor Signaling Regulation Reporting Respiration Rodent Sensory Ganglia Signal Pathway Signal Transduction Spinal Ganglia Stress TRPV1 gene Testing Transgenic Mice allodynia antinociception behavior measurement chronic pain chronic painful condition dorsal horn electrical property experimental study fluorescence imaging healthy aging improved in vivo inflammatory pain injured innovation male mitochondrial membrane mitochondrial metabolism nerve injury neuronal excitability novel overexpression oxidation pain chronification pain relief painful neuropathy patch clamp pharmacologic prescription opioid response sciatic nerve societal costs therapeutic evaluation tissue injury tool transcriptome sequencing

项目摘要

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.

慢性疼痛每年影响超过5000万美国人，导致非凡个人和社会成本。增加困境，涉及处方鸦片的死亡在过去的十年中，镇痛药几乎近三倍。疼痛的临床挑战管理有证据表明慢性疼痛在机械上与急性不同疼痛，因此对分子和细胞机制的透彻理解向慢性疼痛的过渡对于改善和扩大治疗方案至关重要。高温启动是一种令人信服的过渡到慢性疼痛的模型伤害解决了，但使动物处于底漆状态，其中第二次侮辱会诱导A 大大延长疼痛反应。这里提出的实验将检查与急性和慢性炎症性疼痛发展的线粒体动力学相比进行神经性疼痛的神经损伤模型，并将探索介导的分子机制提出的内源性解偶联机制和线粒体的反伤害性作用解偶联药物。特定目标1将检查线粒体功能的变化对有害侮辱的反应以及线粒体调节对急性痛觉过敏的影响感官神经节。特定的目标2将使用斑块夹电生理学来证明变化在对线粒体功能操纵的感觉神经元的电性能中并将确定介导线粒体对神经元影响的细胞信号传导途径兴奋性。特定的目标3将表征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线粒体功能在炎症和神经性疼痛时期。该提议将使用创新方法探索线粒体影响的新型机制急性和慢性疼痛的表现，并测试靶向这些的治疗潜力缓解疼痛的机制。