Sodium channels and electrogenesis in sensory neurons

感觉神经元中的钠通道和电发生

• 批准号: 7345372
• 负责人: THEODORE R CUMMINS
• 金额: $ 29.67万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-19 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7345372
• 关键词: Action Potentials; Address; Adult; Afferent Neurons; Attention; Biolistics; Cells; Chronic; Clinical Research; Cutaneous; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease; Epilepsy; Erythromelalgia; Exhibits; Exposure to; Fire - disasters; Generations; Goals; Gold; Human; In Vitro; Inflammation; Inherited; Injury; Investigation; Medical; Membrane Potentials; Molecular; Muscle; Mutation; Nerve Fibers; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Neuraxis; Neurons; Neuropathy; Pain; Patch-Clamp Techniques; Peripheral; Peripheral Nerves; Peripheral nerve injury; Personal Satisfaction; Phosphorylation; Play; Point Mutation; Property; Protein Isoforms; Protein Kinase; Protein Kinase C; Ramp; Rattus; Recombinants; Research; Resistance; Role; Sensory; Sensory Ganglia; Sensory Physiology; Small Interfering RNA; Sodium; Sodium Channel; Spinal Ganglia; Syndrome; System; Techniques; Tetrodotoxin; Toxin; Viral; bean; chronic pain; inflammatory neuropathic pain; inhibitor/antagonist; injured; mutant; nerve injury; nervous system disorder; neuronal cell body; novel; novel therapeutics; painful neuropathy; voltage

Voltage-gated sodium channels are critical determinants of neuronal and muscle cellular excitability. These channels may also play a crucial role in chronic pain, epilepsy and other neurological disorders. However, investigations into the precise functional role that specific sodium channel isoforms play in normal and abnormal cellular excitability is lacking. A main objective of our research is to identify molecular mechanism(s) underlying alterations in the electrical excitability of sensory neurons. Experimental and clinical studies have clearly shown that the peripheral nerve fibers, and the neuronal cell bodies that give rise to them, can become hyperexcitable after injury and that this hyperexcitability contributes to neuropathic pain. Changes in sodium currents are likely to alter the excitability of sensory neurons, and could contribute to the reduced threshold for repetitive firing and increased level of spontaneous firing that has been observed in injured and inflamed sensory neurons. Subthreshold sodium currents, currents that are active at membrane potentials negative to the threshold for action potential generation, can play crucial roles in regulating electrogenesis in neurons. The present proposal focuses on tetrodotoxin-sensitive subthreshold sodium currents in sensory neurons and their role in chronic pain mechanisms. This project will address the hypothesis that altered sodium currents play a crucial role in the development of enhanced excitability associated with chronic pain with the following specific aims: 1. Characterize the properties of sodium currents in cutaneous afferent dorsal root ganglion neurons acutely isolated from normal adult rats, after chronic peripheral inflammation and after peripheral nerve injury. 2. Determine how specific sodium channel isoforms contribute to sodium currents in control and sensitized neurons. 3. Examine the effect of sodium channel mutations that cause the inherited painful neuropathy primary erythermalgia in humans on Nav1.7 sodium channel properties and excitability in sensory neurons. Understanding the changes that occur in the sodium currents of sensory neurons following inflammation and/or nerve injury and how specific sodium channel isoforms contribute to these changes should enhance our understanding of the normal and abnormal physiology of sensory neurons and should aid the development of new therapeutic strategies for the treatment of pain.

电压门控钠通道是神经元和肌肉细胞兴奋性的关键决定因素。 这些通道也可能在慢性疼痛，癫痫和其他神经系统疾病中发挥关键作用。 然而，对特定钠通道亚型在正常细胞中发挥的确切功能作用的研究， 并且缺乏异常的细胞兴奋性。我们研究的一个主要目标是鉴定分子 感觉神经元电兴奋性改变的潜在机制。实验和 临床研究已经清楚地表明，周围神经纤维和神经元细胞体， 对他们来说，在受伤后会变得过度兴奋，这种过度兴奋有助于神经病理性 痛苦钠电流的变化可能会改变感觉神经元的兴奋性， 重复性放电阈值降低，自发性放电水平增加， 在受伤和发炎的感觉神经元中观察到。阈下钠电流，在 膜电位负于动作电位产生的阈值，可以在 调节神经元中的电发生。目前的建议集中在河豚毒素敏感的亚阈值 感觉神经元的钠电流及其在慢性疼痛机制中的作用。 这个项目将解决的假设，改变钠电流发挥了至关重要的作用， 发展与慢性疼痛相关的增强的兴奋性，具有以下特定目的：1. 皮肤传入背根神经节神经元钠电流的性质 分离自正常成年大鼠、慢性外周炎症后和外周神经损伤后。2. 确定特定的钠通道亚型如何在对照和致敏中对钠电流做出贡献 神经元3.检查导致遗传性疼痛性神经病的钠通道突变的影响 在感觉神经元中的Nav1.7钠通道特性和兴奋性。 了解炎症后感觉神经元钠电流的变化 和/或神经损伤，以及特定钠通道亚型如何促成这些变化， 我们对感觉神经元的正常和异常生理学的理解， 开发用于治疗疼痛的新治疗策略。