Regulation of excitatory ion channels in spinal cord dorsal horn pain signalling

脊髓背角疼痛信号传导中兴奋性离子通道的调节

• 批准号: RGPIN-2014-06044
• 负责人: Hildebrand, Michael
• 金额: $ 2.55万
• 依托单位: Carleton University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=653563
• 关键词: Regulation; excitatory; ion; channels; spinal

The dorsal horn of the spinal cord is an essential component of the pain transmission pathway. The outer layers of the dorsal horn process information from peripheral pain sensing neurons and relay integrated signals up to brain pain centers. Enhanced dorsal horn output underlies pain hypersensitivity in many chronic pain conditions, and yet the molecular and cellular mechanisms which cause this spinal cord dysfunction are poorly understood. The excitability of individual dorsal horn neurons is controlled by a balance between neuronal excitation (the "gas pedal" for pain sensation) and inhibition (the "brake pedal" for pain sensation), with shifts in this balance leading to hyperexcitability and pathological pain. We will study the role of electrical proteins, called ion channels, in regulating neuronal excitation within the spinal cord dorsal horn. Different types of dorsal horn neurons play different roles in spinal cord pain processing and we will investigate how variations in ion channel activity enable this specialization within the pain signalling network. To accomplish this, we will study the activity of specific types of ion channels in rodent spinal cord neurons through a combination of electrical recordings and molecular, biochemical and pharmacological techniques. Our research team will then investigate the molecular and cellular signalling mechanisms that increase excitatory ion channel activity to cause enhanced spinal cord excitation and pain hypersensitivity. Susceptibility to spinal cord hyperexcitability and chronic pain increases with age. We will identify how changes in ion channel expression and function contribute to the increased prevalence of chronic pain at later stages of development. Thus, our research program will provide critical information for understanding spinal pain processing, including how molecular changes in the pain signalling network can lead to pathological pain. These discoveries will help identify which pain-producing molecules are best suited as potential targets for new pain treatments. Our ultimate goal is to partner with industry to translate these findings into biomedical innovation which will help the millions of Canadians suffering from poorly-managed pain. The training of scientists throughout this research program will provide Canada with highly skilled workers equipped for careers in industrial, academic, health, and government professions. These personnel will increase Canada's competitiveness in a knowledge-based global economy.

脊髓背角是疼痛传递途径的重要组成部分。 背角的外层处理来自外周痛觉神经元的信息，并将整合的信号传递到大脑疼痛中心。 增强的背角输出是许多慢性疼痛病症中疼痛超敏反应的基础，但导致这种脊髓功能障碍的分子和细胞机制仍知之甚少。 单个背角神经元的兴奋性由神经元兴奋（痛觉的“油门踏板”）和抑制（痛觉的“刹车踏板”）之间的平衡控制，这种平衡的变化导致过度兴奋和病理性疼痛。 我们将研究电蛋白，称为离子通道，在调节脊髓背角神经元兴奋的作用。 不同类型的背角神经元在脊髓疼痛处理中发挥不同的作用，我们将研究离子通道活性的变化如何使疼痛信号网络中的这种专业化。 为了实现这一目标，我们将通过电记录和分子，生物化学和药理学技术的组合来研究啮齿动物脊髓神经元中特定类型的离子通道的活性。 我们的研究小组将研究增加兴奋性离子通道活性的分子和细胞信号机制，从而引起脊髓兴奋和疼痛超敏反应的增强。 随着年龄的增长，脊髓过度兴奋和慢性疼痛的易感性增加。 我们将确定离子通道表达和功能的变化如何在发展的后期阶段增加慢性疼痛的患病率。 因此，我们的研究计划将为理解脊柱疼痛过程提供关键信息，包括疼痛信号网络中的分子变化如何导致病理性疼痛。 这些发现将有助于确定哪些产生疼痛的分子最适合作为新疼痛治疗的潜在靶点。 我们的最终目标是与业界合作，将这些发现转化为生物医学创新，帮助数百万患有管理不善疼痛的加拿大人。 在整个研究计划中，科学家的培训将为加拿大提供高技能的工人，为工业，学术，卫生和政府专业的职业生涯做好准备。 这些人员将提高加拿大在以知识为基础的全球经济中的竞争力。