Sodium channels and electrogenesis in sensory neurons

描述(由申请人提供)：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，对于特定的钠通道异构体在正常和异常细胞兴奋性中所起的确切功能作用的研究还很缺乏。我们研究的一个主要目的是确定感觉神经元电兴奋性改变的分子机制(S)。实验和临床研究清楚地表明，周围神经纤维和产生它们的神经元胞体在损伤后可以变得过度兴奋，这种过度兴奋导致神经病理性疼痛。钠电流的变化可能改变感觉神经元的兴奋性，并可能导致重复放电阈值降低和自发放电水平增加，这已在受损和炎症的感觉神经元中观察到。亚阈值钠电流，即在膜电位负于动作电位产生阈值时激活的电流，在调节神经元的电生成过程中发挥着至关重要的作用。目前的建议集中在感觉神经元上对河豚毒素敏感的阈值下钠电流及其在慢性疼痛机制中的作用。本项目将解决这一假说，即改变的钠电流在与慢性疼痛相关的兴奋性增强的发展中起关键作用，具体目的如下：1.从正常成年大鼠急性分离的皮肤传入背根节神经元钠电流的特性，在慢性外周炎症和周围神经损伤后。2.确定特定的钠通道异构体如何对控制神经元和致敏神经元的钠电流做出贡献。3.研究导致人类遗传性痛性神经病原发红热性疼痛的钠通道突变对感觉神经元NA1.7钠通道特性和兴奋性的影响。了解炎症和/或神经损伤后感觉神经元钠电流的变化，以及特定的钠通道亚型如何参与这些变化，将有助于我们理解感觉神经元的正常和异常生理，并有助于开发新的治疗策略来治疗疼痛。

DESCRIPTION (provided by applicant): 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.