Sodium channels and electrogenesis in sensory neurons

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、癫痫和其他神经疾病中发挥关键作用。 然而，对特定的钠通道亚型在正常人中所起的精确功能作用的研究 而且缺乏异常的细胞兴奋性。我们研究的一个主要目标是识别分子 感觉神经元电兴奋性变化的潜在机制(S)。试验性和 临床研究清楚地表明，周围神经纤维和产生的神经元胞体 对他们来说，受伤后会变得过度兴奋，这种过度兴奋会导致神经病变 疼痛。钠电流的变化可能会改变感觉神经元的兴奋性，并可能起到作用。 到重复发射阈值的降低和自发发射水平的增加 在受损和发炎的感觉神经元中观察到。亚阈值钠电流，在 膜电位负于动作电位产生的阈值，可在 调节神经元中的电生成。本提案侧重于对河豚毒素敏感的亚阈值 感觉神经元钠电流及其在慢性疼痛机制中的作用。 这个项目将解决这一假说，即改变的钠电流在 发展与慢性疼痛相关的增强兴奋性，具体目标如下：1. 急性刻画皮肤背根神经节传入神经元钠电流特性 分离自正常成年大鼠，慢性外周炎症后和周围神经损伤后。2. 确定特定的钠通道异构体如何在对照和敏化的钠电流中起作用 神经元。3.研究导致遗传性痛性神经病的钠通道突变的影响 人类原发性红热痛对感觉神经元NA1.7钠通道特性和兴奋性的影响。 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的钠通道亚型如何促进这些变化 我们对感觉神经元的正常和异常生理的理解，应该有助于 为治疗疼痛开发新的治疗策略。

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.