Nociceptive Mechanisms Underlying Sickle Cell Pain

镰状细胞疼痛背后的伤害机制

• 批准号: 8708438
• 负责人: Cheryl A Hillery
• 金额: $ 39.54万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708438
• 关键词: Acute; Adult; Afferent Neurons; Age; Ankyrins; Antioxidants; Behavior; Behavioral; Bioenergetics; Blood Vessels; Buffers; Characteristics; Child; Chronic; Complex; Data; Development; Diabetic Neuropathies; Disease; Erythrocytes; Exhibits; Fiber; Frequencies; Functional disorder; Gene Expression; Generations; Genes; Goals; Grant; Health; Human; Hypersensitivity; Hypoxia; In Situ; In Vitro; Inborn Genetic Diseases; Ion Channel; Ions; Laboratories; Lead; Mechanics; Mediating; Membrane; Methods; Mitochondria; Modeling; Molecular Profiling; Morphology; Mus; Neurons; Nociception; Oxidative Stress; Oxygen Consumption; Pain; Pathway interactions; Patients; Reactive Oxygen Species; Reperfusion Injury; Sensory; Severities; Shapes; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Spinal; Spinal Ganglia; Stress; Syndrome; Time; Vanilloid; behavior change; chemotherapy induced neuropathy; chronic pain; disability; heat stimulus; improved; in vivo; mitochondrial dysfunction; neuronal cell body; neutrophil; new therapeutic target; pain behavior; receptor; response; restoration; sickling; spontaneous pain

DESCRIPTION (provided by applicant): The overall goal of this project is to determine the contribution of sensory neuron mitochondrial dysfunction and TRP channel sensitization to pain in sickle cell disease (SCD), including the development of chronic pain. SCD is accompanied by crippling pain during acute sickling episodes that increases in severity and frequency with age. By adulthood, approximately 50% of SCD patients also suffer from chronic pain. SCD involves repeated ischemia-reperfusion injury and increased neutrophil numbers/activity, which results in elevated reactive oxygen species (ROS) generation and oxidative stress. This can lead to mitochondrial dysfunction and sensitization of Transient Receptor Potential (TRP) ion channels. We show that mice with severe SCD exhibit evidence for ongoing pain and pronounced pain-like behavior in response to cold, mechanical and heat stimuli. Our preliminary data also indicate that sensory neurons from sickle mice have severely dysfunctional mitochondria. We hypothesize that ROS and oxidative stress induce mitochondrial dysfunction and TRP channel sensitization in sickle sensory neurons, leading to the chronic pain and thermal hypersensitivity that is characteristic of this devastating disease. Aim 1 will determine the time course of neuronal mitochondrial dysfunction and pain sensitivity in sickle mice from age 2 to 12 weeks. Aim 2 will determine whether sensitized TRPA1 or TRPM8 channels underlie the cold hypersensitivity and primary afferent sensitization in sickle mice. Aim 3 will determine whether treatment with mitochondrial-targeted antioxidants reverses the pain behavior and primary afferent sensitization in sickle mice. These interrelated Aims provide a multifaceted approach that will define the mechanisms by which mitochondrial dysfunction and TRP channel sensitization lead to the devastating pain observed in SCD. Furthermore, this study targets specific cold-sensitive ion channels (TRPA1 and TRPM8) on sensory neurons because cold pain and cold hypersensitivity are a major complaint of patients with SCD. Data from this study will improve our understanding of the complex SCD pain syndromes and should aid in identifying novel therapeutic targets

描述（由申请人提供）：本项目的总体目标是确定感觉神经元线粒体功能障碍和TRP通道敏化对镰状细胞病（SCD）疼痛的贡献，包括慢性疼痛的发展。SCD在急性镰状病发作期间伴随着严重程度和频率随年龄增加的致残性疼痛。到成年时，大约50%的SCD患者也患有慢性疼痛。SCD涉及反复缺血-再灌注损伤和增加的中性粒细胞数量/活性，这导致活性氧（ROS）产生和氧化应激升高。这可导致线粒体功能障碍和瞬时受体电位（TRP）离子通道的敏化。我们发现，患有严重SCD的小鼠表现出持续疼痛的证据，并对冷，机械和热刺激做出明显的疼痛样行为。我们的初步数据还表明，镰状小鼠的感觉神经元有严重功能失调的线粒体。我们假设ROS和氧化应激诱导镰状感觉神经元的线粒体功能障碍和TRP通道敏化，导致慢性疼痛和热超敏反应，这是这种毁灭性疾病的特征。目的1将确定2 - 12周龄镰状小鼠神经元线粒体功能障碍和疼痛敏感性的时间过程。目的2：探讨致敏的TRPA 1或TRPM 8通道是否是镰刀型小鼠冷超敏反应和初级传入致敏的基础。目的3将确定是否治疗与神经靶向抗氧化剂逆转疼痛行为和初级传入致敏镰状小鼠。这些相互关联的目标提供了一个多方面的方法，将定义线粒体功能障碍和TRP通道敏化导致SCD中观察到的毁灭性疼痛的机制。此外，这项研究针对感觉神经元上的特定冷敏感离子通道（TRPA 1和TRPM 8），因为冷痛和冷超敏反应是SCD患者的主要主诉。这项研究的数据将提高我们对复杂SCD疼痛综合征的理解，并有助于确定新的治疗靶点