Spinal Microglial Mechanisms of Visceral Hypersensitivity

内脏过敏的脊髓小胶质细胞机制

• 批准号: 7790438
• 负责人: Carl Y Saab
• 金额: $ 24.16万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7790438
• 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' s disease; Data; Diffusion; Esthesia; Future; Genus Cola; 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; 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

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）：来自内脏器官（如胃或肠）的疼痛是一种病理警报，例如，与炎症性肠病（包括克罗恩病和溃疡性结肠炎）相关的疼痛。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难治性内脏疼痛。在大鼠结肠炎模型中，我们建议通过阻断中枢神经系统中新的细胞和分子靶点，在行为和神经元水平上逆转伤害感觉的迹象。我们假设，在实验性结肠炎大鼠中，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，而不是脊髓的其他细胞类型，选择性地表达应激激活蛋白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的高兴奋性和内脏伤害感觉的行为迹象。这些研究将帮助我们开始确定远程（脊髓内）和不同于初始病理器官（结肠）的药物干预部位，以提高生物治疗的镇痛效力，同时最大限度地减少不良副作用。