Spinal glia activation in chronic stress-induced visceral hyperalgesia

慢性应激引起的内脏痛觉过敏中的脊髓胶质细胞激活

• 批准号: 8230795
• 负责人: SYLVIE BRADESI
• 金额: $ 20.94万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230795
• 关键词: Address; Affect; Agonist; Antisense Oligonucleotides; Behavior assessment; Cells; Chest Pain; Chronic; Chronic stress; Clinical; Coculture Techniques; Data; Development; Disease; Endocrine; Enzyme-Linked Immunosorbent Assay; Equilibrium; Event; Exhibits; Experimental Animal Model; Experimental Designs; Experimental Models; Exposure to; Fibromyalgia; Functional Gastrointestinal Disorders; Glucocorticoids; Glutamate Transporter; Glutamates; Goals; Health; Hyperalgesia; Hypersensitivity; Immune; Immune system; Immunohistochemistry; In Vitro; Inflammation; Interneurons; Interstitial Cystitis; Intestines; Irritable Bowel Syndrome; Link; Maintenance; Mediating; Mediator of activation protein; Modeling; Molecular; N-Methylaspartate; NR1 gene; Neuraxis; Neurobiology; Neuroglia; Neurons; Nociception; Pain; Pathway interactions; Pattern; Peripheral; Persistent pain; Pharmacological Treatment; Play; Rattus; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Injuries; Spinal nerve structure; Stress; Substance P; Symptoms; Synapses; Syndrome; System; TACR1 gene; Testing; Time; Visceral; Visceral pain; Water; Western Blotting; attenuation; base; chronic pain; colorectal distension; dorsal horn; effective therapy; immune activation; inhibitor/antagonist; innovation; knockout animal; nerve injury; new therapeutic target; novel; novel strategies; relating to nervous system; response; sensory system

DESCRIPTION (provided by applicant): The current proposal, for the first time, addresses the role of neuro-immune activation within the central nervous system as a plausible mechanism underlying the visceral pain component of many common functional gastrointestinal disorders (FGID) including irritable bowel syndrome (IBS). Although increasing evidence has emerged for the role of spinal glia in the mechanisms mediating persistent pain, its implication in visceral pain has not been evaluated. We propose the general hypothesis that chronic stress, known as a key factor in the first onset or exacerbation of IBS symptoms, triggers the activation of a spinal network comprising neurons and immune cells (glia), playing a central role in the modulation of visceral nociception. Using a rat model of chronic water avoidance stress, we propose to characterize the role of stress-induced spinal glia activation in the modulation of visceral sensitivity and determine the molecular pathways engaged in the initiation and maintenance of visceral hyperalgesia. Our first specific aim is to assess the temporal profile of spinal glia activation during and after chronic stress and to test the ability of inhibitors specific of glia to reduce stress- induced visceral hyperalgesia. The second specific aim relates to the characterization of molecular mechanisms linking chronic stress and spinal glial activation. The experimental design proposed in this application includes the behavioral assessment of visceral sensitivity in response to different pharmacological treatments (antagonists, agonists, oligonucleotide antisenses), combined with in vitro analysis using Western blotting, multiplex ELISA, immunohistochemistry and quantitative RT-PCR. The long-term goal of the proposed studies is the characterization of signaling pathways underlying the observed endocrine-neural- immune interactions using selective knockout animals and glia/neurons co-cultures. Targeting specific mediators of the glial-neuronal crosstalk may provide an innovative approach for the development of novel therapeutic targets for the treatment of chronic pain conditions associated with enhanced stress responsiveness. The concept of stress-induced modulation of glial-neurons signaling and its implication in long-term alteration of the sensory system may be generalized to many other stress-sensitive pain conditions, including interstitial cystitis, non-cardiac chest pain and fibromyalgia. PUBLIC HEALTH RELEVANCE: In the current proposal, we have developed the concept that chronic stress may induce activation of the immune system in the spinal cord, initiating a cascade of events that will affect the sensory system. This new approach has considerable implication for the development of novel therapeutic targets for the treatment of chronic pain conditions associated with enhanced stress responsiveness, including functional gastrointestinal disorders, for which effective treatment remains a clinical challenge.

描述（由申请人提供）：当前的提案首次阐述了中枢神经系统内神经免疫激活的作用，作为许多常见功能性胃肠道疾病（FGID）（包括肠易激综合征（IBS））内脏疼痛成分的潜在机制。尽管越来越多的证据表明脊髓神经胶质细胞在介导持续性疼痛的机制中发挥作用，但其在内脏疼痛中的作用尚未得到评估。我们提出一般假设，即慢性压力被认为是IBS症状首次发作或恶化的关键因素，它会触发由神经元和免疫细胞（神经胶质细胞）组成的脊柱网络的激活，在内脏伤害感受的调节中发挥核心作用。使用慢性回避水应激的大鼠模型，我们建议描述应激诱导的脊髓神经胶质细胞激活在内脏敏感性调节中的作用，并确定参与内脏痛觉过敏的启动和维持的分子途径。我们的第一个具体目标是评估慢性应激期间和之后脊髓神经胶质细胞激活的时间分布，并测试神经胶质细胞特异性抑制剂减少应激诱导的内脏痛觉过敏的能力。第二个具体目标涉及慢性应激和脊髓神经胶质细胞激活之间的分子机制的表征。本申请提出的实验设计包括响应不同药物治疗（拮抗剂、激动剂、寡核苷酸反义）的内脏敏感性的行为评估，并结合使用蛋白质印迹、多重ELISA、免疫组织化学和定量RT-PCR的体外分析。拟议研究的长期目标是利用选择性敲除动物和神经胶质细胞/神经元共培养物来表征观察到的内分泌-神经-免疫相互作用背后的信号通路。针对神经胶质-神经元串扰的特定介质可能为开发新的治疗靶点提供创新方法，用于治疗与增强的应激反应相关的慢性疼痛。应激诱导的神经胶质神经元信号调节的概念及其对感觉系统长期改变的影响可以推广到许多其他应激敏感疼痛病症，包括间质性膀胱炎、非心源性胸痛和纤维肌痛。公共健康相关性：在当前的提案中，我们提出了这样的概念：慢性压力可能会诱导脊髓中免疫系统的激活，引发一系列影响感觉系统的事件。这种新方法对于开发新的治疗靶点具有相当大的意义，用于治疗与应激反应性增强相关的慢性疼痛，包括功能性胃肠道疾病，有效治疗仍然是临床挑战。