Neural and Chemical Basis of Pathological Pain

病理性疼痛的神经和化学基础

• 批准号: 8991249
• 负责人: Jun-Ming Zhang
• 金额: $ 39.39万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8991249
• 关键词: Acute; Affect; Afferent Neurons; Animals; Attention; Back; Back Pain; Behavior; Behavior assessment; Behavioral; Cells; Chemicals; Chronic; Data; Development; Electrophysiology (science); Frequencies; Ganglia; Generations; Goals; Health; Healthcare; Human; Hypersensitivity; In Vitro; Inflammation; Inflammation Mediators; Inflammation Process; Inflammatory; Injection of therapeutic agent; Interleukin-8; Intervertebral disc structure; Laboratories; Link; Low Back Pain; Mechanics; Mediating; Methods; Microscopy; Modeling; Molecular; Morbidity - disease rate; Motor; Mus; Neurons; Pain; Patients; Pattern; Pharmaceutical Preparations; Play; Pre-Clinical Model; Process; Productivity; Property; Protein Isoforms; Rattus; Research; Role; SCN8A gene; Sensory; Sensory Ganglia; Small Interfering RNA; Societies; Sodium; Sodium Channel; Spinal Ganglia; Syndrome; Techniques; Testing; United States; Wages; Work; analog; base; behavior measurement; chemokine; chemotherapy; chronic pain; cost; cytokine; human subject; in vivo; interest; knock-down; neuronal excitability; neuropeptide Y; new therapeutic target; novel; oxaliplatin; pain behavior; painful neuropathy; pre-clinical; receptor; relating to nervous system; therapeutic target

DESCRIPTION (provided by applicant): Low back pain is a common problem with high morbidity costs to society, and many patients receive little relief from current therapies. Abnormal spontaneous activity of sensory neurons plays a key role in establishing the chronic pain state in a preclinical model relevant to low back pain, in which pain behaviors are induced by locally inflaming the lumbar dorsal root ganglion (DRG). This activity depends on a particular sodium channel isoform, Nav1.6, which can mediate persistent and resurgent sodium currents that in turn can underlie high- frequency/bursting activity. To date this channel has been largely ignored as a therapeutic target; however, knocking down this channel in the DRG in vivo with small interfering RNA can completely block development of pain behaviors induced by local DRG inflammation, without affecting behavior in the normal animal or motor function. Molecules involved in the inflammation process, such as cytokines/chemokines, have direct effects on sensory neuron excitability and pain. However, the underlying mechanisms are largely unexplored. We hypothesize that local inflammation of the DRG increases expression/release of inflammatory cytokines and enhances high-frequency/bursting discharges by regulating Nav1.6 in a subset of sensory neurons and leads to pain and hypersensitivity. The hypothesis will be tested in 3 Specific Aims: 1) Characterize functional and properties and anatomical distributions of Nav1.6 sodium channel in normal and inflamed sensory ganglia, testing the hypothesis that this channel plays a crucial role in abnormal spontaneous activity by mediating persistent and resurgent currents. Immunostaining methods will be used to test the hypothesis that bursting cells in inflamed ganglia are enriched in Nav1.6+ neurons and in molecules previously linked to pain, such as neuropeptide Y and CGRP. 2) Determine how pro-inflammatory cytokines regulate functional properties of Nav1.6 and Nav1.6-mediated spontaneous activity. We hypothesize that GRO/KC, a chemokine that is up- regulated in several pain models and in human patients with wide-spread pain syndromes, acts to increase spontaneous activity by regulating Nav1.6. 3) Assess the role of Nav1.6 in pathological pain. We will use novel behavioral assessment methods combined with local siRNA knockdown, and selective pharmacological block to determine whether this channel plays a role in the development and persistence of pain after DRG inflammation. Additionally, it will be tested in another back pain model and in a model of neuropathic pain. These aims will be carried out using combined electrophysiological, behavioral, microscopy, and molecular methods. In particular, our laboratory's newly established techniques of manipulating the sensory ganglia in vivo with drugs or small interfering RNAs, in a highly localized fashion, combined with behavioral measurements and electrophysiology, provide a powerful integrated approach to understanding chronic pain mechanisms. Because inflammatory processes play a role in many types of chronic pain, the findings will be relevant not only to understanding low back pain, but other types of pain as well.

描述（由申请人提供）：腰痛是社会发病率高的常见问题，许多患者几乎没有得到当前疗法的缓解。感觉神经元的异常自发活性在与下背痛有关的临床前模型中建立慢性疼痛状态方面起着关键作用，在这种模型中，疼痛行为是通过局部发炎的腰部背侧根神经节（DRG）引起的。该活性取决于特定的钠通道同工型NAV1.6，它可以介导持续和复兴的钠电流，而钠电流又可以是高频/爆发活性的基础。迄今为止，此通道在很大程度上被忽略为治疗靶点。但是，用小的干扰RNA在体内敲击DRG中的该通道可以完全阻止局部DRG炎症引起的疼痛行为的发展，而不会影响正常动物或运动功能的行为。参与炎症过程的分子，例如细胞因子/趋化因子，对感觉神经元兴奋性和疼痛有直接影响。但是，基本的机制在很大程度上没有探索。我们假设DRG的局部炎症会增加炎症细胞因子的表达/释放，并通过调节感觉神经元的子集中的NAV1.6来增强高频/爆发放电，并导致疼痛和高敏性。该假设将以3个特定目的进行检验：1）表征在正常和发炎的感觉神经节中NAV1.6钠通道的功能和特性以及解剖分布，检验了以下假设：该通道通过介导持续和复苏的水流中介导持续和复兴的自发活性中起着至关重要的作用。免疫染色方法将用于检验以下假设：发炎神经节中的爆发细胞富含NAV1.6+神经元和先前与疼痛有关的分子（例如神经肽Y和CGRP）。 2）确定促炎性细胞因子如何调节NAV1.6和NAV1.6介导的自发活性的功能特性。我们假设GRO/KC是一种在多种疼痛模型中受到调节的趋化因子和广泛疼痛综合征的人类的调节，可通过调节NAV1.6来增加自发活性。 3）评估NAV1.6在病理疼痛中的作用。我们将使用新型的行为评估方法与局部siRNA敲低和选择性的药理阻滞相结合，以确定该通道在DRG炎症后是否在疼痛的发育和持续性中起作用。此外，将在另一个背痛模型和神经性疼痛模型中进行测试。这些目标将使用联合电生理，行为，显微镜和分子方法进行。特别是，我们实验室的新建立的技术是用药物或小型干扰RNA以高度本地化的方式连同行为测量和电生理学相结合，为理解慢性疼痛机制的理解提供了强大的综合方法。由于炎症过程在许多类型的慢性疼痛中起作用，因此这些发现不仅与理解腰痛，而且还与其他类型的疼痛有关。