Spinal Microglial Mechanisms of Visceral Hypersensitivity

内脏过敏的脊髓小胶质细胞机制

基本信息

批准号：
8063605
负责人：
Carl Y Saab
金额：
$ 18.88万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8063605
关键词：
Abbreviations Abdominal Muscles Action Potentials Adenosine Triphosphate Adverse effects Affect Afferent Neurons Analgesics Anti-Inflammatory Agents Anti-inflammatory Astrocytes Attenuated Behavior Behavioral Biological Response Modifier Therapy Catheters Cells Chronic Phase Colitis Colon Crohn&apos s disease Data Diffusion Esthesia Future Host Defense Hypersensitivity Individual Inflammation Inflammation Mediators Inflammatory Bowel Diseases Injection of therapeutic agent Injury Intervention Intestines Literature Location MAP Kinase Gene MAPK14 gene Maintenance Measures Mediating Microglia Modeling Molecular Molecular Target Neuraxis Neuroglia Neurons Neuropathy Nociception Organ Pain Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Property Proteins Publishing Purinoceptor Rattus Reflex action Research Personnel Rest Role Signal Pathway Signal Transduction Site Spinal Spinal Cord Staining method Stains Stomach Stress Testing Therapeutic Trinitrobenzenesulfonic Acid Ulcerative Colitis United States Validation Visceral Visceral pain cell type cellular targeting colorectal distension extracellular human MAPK14 protein immunogenic improved inhibitor/antagonist innovation interdisciplinary approach irritation macrophage neuron development novel pain behavior public health relevance receptor research study response selective expression

项目摘要

DESCRIPTION (provided by applicant): Pain originating from visceral organs such as stomach or intestine is an alarm of pathology, for example, pain associated with inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. Despite recent advances in the treatment of colitis using systemic or local anti-inflammatory therapies, many patients still complain of intractable visceral pain. In a rat model of colitis, we propose to reverse signs of nociception at behavioral and neuronal levels by blocking novel cellular and molecular targets in the central nervous system. We hypothesize that, in rats with experimental colitis, immunogenic microglial cells in the spinal cord become activated and release pro-inflammatory mediators, which then enhance the excitability of visceral sensory neurons, leading to nociceptive behavior. We further hypothesize that activated microglia, but not other cell types of the spinal cord, selectively express the stress-activated protein p38 and adenosine triphosphate receptor P2X4, whereas blocking these signaling pathways attenuates neuronal hyperexcitability and behavioral signs of visceral nociception. These studies will help us begin to define sites for pharmacologic interventions that are remote (within the spinal cord) and distinct from the organ of initial pathology (the colon) to improve the analgesic potency of biologic therapies, while minimizing undesirable side effects. PUBLIC HEALTH RELEVANCE: Inflammation or injury to a visceral organ (an 'internal' organ like stomach or gut) is often associated with unpleasant visceral sensation of pain. Certain forms of visceral pain, such as that induced by colon inflammation, cannot be effectively managed. To ameliorate treatment options for intractable visceral pain, we show in this application preliminary evidence for successful reversal of pain behavior in rats with colitis by blocking novel cellular and molecular targets in the spinal cord. Unique features of our proposal include the remote location of these targets from the site of colon inflammation, the multidisciplinary approach, and the diversified expertise of our team of investigators.

描述（由申请人提供）：源自内脏器官（例如胃或肠）的疼痛是病理警报，例如与炎症性肠病相关的疼痛，包括克罗恩病和溃疡性结肠炎。尽管最近在使用全身或局部抗炎疗法治疗结肠炎方面取得了进展，但许多患者仍然抱怨顽固性内脏疼痛。在结肠炎大鼠模型中，我们建议通过阻断中枢神经系统中的新细胞和分子靶点来逆转行为和神经元水平上的伤害感受迹象。我们假设，在患有实验性结肠炎的大鼠中，脊髓中的免疫原性小胶质细胞被激活并释放促炎介质，然后增强内脏感觉神经元的兴奋性，导致伤害性行为。我们进一步假设，激活的小胶质细胞（而非脊髓的其他细胞类型）选择性表达应激激活蛋白 p38 和三磷酸腺苷受体 P2X4，而阻断这些信号通路会减弱神经元过度兴奋和内脏伤害感受的行为迹象。这些研究将帮助我们开始确定远离（脊髓内）且与初始病理器官（结肠）不同的药物干预部位，以提高生物疗法的镇痛效力，同时最大限度地减少不良副作用。公共卫生相关性：内脏器官（胃或肠道等“内部”器官）的炎症或损伤通常与令人不快的内脏疼痛感相关。某些形式的内脏疼痛，例如由结肠炎症引起的内脏疼痛，无法得到有效控制。为了改善顽固性内脏疼痛的治疗选择，我们在本申请中展示了通过阻断脊髓中新的细胞和分子靶点成功逆转结肠炎大鼠疼痛行为的初步证据。我们提案的独特之处包括这些目标距离结肠炎症部位较远、多学科方法以及我们研究团队的多元化专业知识。