Role of Microglia in Chronic Visceral Pain

小胶质细胞在慢性内脏疼痛中的作用

• 批准号: 7849058
• 负责人: ELIE D AL-CHAER
• 金额: $ 18.35万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849058
• 关键词: Abbreviations; Abdominal Muscles; Acute; Adult; Adverse effects; Affect; Afferent Neurons; Analgesics; Animal Model; Astrocytes; Behavior; Behavioral; Biological Response Modifier Therapy; Cations; Cells; Characteristics; Chronic; Clinical; Colon; Data; Digestive System Disorders; Disease; Effectiveness; Exhibits; External Oblique Muscle; Family; Future; Genus Cola; Homeostasis; Host Defense; Hypersensitivity; ITGAM gene; Immune response; Immunohistochemistry; Inflammation; Inflammation Mediators; Injury; Intervention; Intrathecal Injections; Irritable Bowel Syndrome; Label; Ligands; Location; MAPK14 gene; Macrophage Activation; Microglia; Minocycline; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Target; Motor; Neonatal; Neuraxis; Neuroglia; Neurons; Neuropathy; Nociception; Organ; Pain; Pathway interactions; Patients; Phenotype; Population; Proteins; Purinoceptor; Rattus; Reflex action; Research Personnel; Residual state; Rest; Rodent Model; Role; Signal Pathway; Signal Transduction; Site; Spinal Cord; Symptoms; Testing; Time; Tissues; Trauma; Visceral; Visceral pain; Western Blotting; behavior measurement; cell type; colorectal distension; conventional therapy; design; improved; inhibitor/antagonist; interdisciplinary approach; intraperitoneal; irritation; neuronal excitability; novel; pain behavior; postnatal; public health relevance; receptor; research study; response

DESCRIPTION (provided by applicant): Hypersensitivity of visceral organs is a main characteristic of numerous functional digestive disorders including irritable bowel syndrome (IBS): a debilitating disorder that affects up to 15% of the US population and one that continues to present a vexing clinical challenge. Despite the large body of scientific studies that have examined its mechanisms, visceral hypersensitivity (VH) evolves in many cases into a chronic condition recalcitrant to conventional treatment. To better understand the mechanisms of chronic VH, we developed an animal model in which rats exhibit symptoms of chronic VH and neuronal hyperexcitability in the absence of obvious colon inflammation. The model is induced by colon irritation (CI) in neonatal rats and results in a consequent symptomatology that carries into adulthood. Using rats with CI, we recently noted a novel host immune response, characterized by activation of macrophage-like cells in the spinal cord called microglia. Inhibiting microglial activation by systemic administration of minocycline or by intrathecal application of TNP- ATP to block P2X4 receptors (ligand-gated cation channels activated by ATP and expressed in the spinal cord exclusively by hyperactive microglia) reversed VH in adult rats treated with neonatal CI. Our observation is intriguing on two levels: 1) it demonstrates microglial activation several months following neonatal colonic insult (at postnatal day PND 120), and 2) it reveals, for the first time, evidence for a microglial role in visceral pain. Therefore, in this proposal we hypothesize that hyperactive microglia contribute to chronic VH and neuronal hyperexcitability in the spinal cord. First, we propose to establish a correlation between VH and a hyperactive phenotype of microglia in rats with CI by identifying molecular targets selective for hyperactive microglia, and second, we propose to reverse neuronal hyperexcitability and chronic VH by suppressing microglial activation using minocycline or by selectively blocking phosphorylated-p38 and P2X4 receptors, two targets specifically expressed on hyperactive microglia. These studies will help expand the targets of pharmacological intervention to non-neuronal sites within the spinal cord, and improve the analgesic potency of biologic therapies, while minimizing undesirable side effects. PUBLIC HEALTH RELEVANCE Visceral pain is a hallmark of many gastroenterological ailments such as irritable bowel syndrome. It may be caused by acute inflammation of an internal organ or be residual to previous injury; its consequences can be debilitating to the patients and to their families and frustrating to the treating clinician. To ameliorate treatment options and renew the hope of many patients with intractable visceral pain, we show in this application preliminary evidence for successful reversal of pain behavior in rats with chronic visceral pain 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 the initial injury, the interdisciplinary approach, and the diversified expertise of our team of investigators.

描述（由申请人提供）：内脏器官过敏是许多功能性消化疾病的主要特征，包括肠易激综合征 (IBS)：一种影响多达 15% 的美国人口的衰弱性疾病，并且持续带来令人烦恼的临床挑战。尽管有大量科学研究对其机制进行了检验，但内脏超敏反应 (VH) 在许多情况下会演变成一种传统治疗难以抵抗的慢性疾病。为了更好地了解慢性 VH 的机制，我们开发了一种动物模型，其中大鼠在没有明显结肠炎症的情况下表现出慢性 VH 和神经元过度兴奋的症状。该模型是通过新生大鼠的结肠刺激（CI）诱导的，并导致随后的症状，并持续到成年。通过使用患有 CI 的大鼠，我们最近注意到一种新的宿主免疫反应，其特征是脊髓中称为小胶质细胞的巨噬细胞样细胞的激活。通过全身施用米诺环素或鞘内应用 TNP-ATP 来阻断 P2X4 受体（由 ATP 激活的配体门控阳离子通道，并仅由活跃的小胶质细胞在脊髓中表达）来抑制小胶质细胞活化，可逆转接受新生 CI 治疗的成年大鼠的 VH。我们的观察在两个层面上很有趣：1）它证明了新生儿结肠损伤（出生后第 120 天）几个月后小胶质细胞的激活，2）它首次揭示了小胶质细胞在内脏疼痛中发挥作用的证据。因此，在本提案中，我们假设过度活跃的小胶质细胞导致脊髓中的慢性 VH 和神经元过度兴奋。首先，我们建议通过识别对小胶质细胞过度活跃的选择性分子靶标，建立 VH 与 CI 大鼠小胶质细胞过度活跃表型之间的相关性；其次，我们建议通过使用米诺环素抑制小胶质细胞活化或通过选择性阻断磷酸化 p38 和 P2X4 受体（两个目标）来逆转神经元过度兴奋和慢性 VH 特异性表达于过度活跃的小胶质细胞上。这些研究将有助于将药物干预的目标扩大到脊髓内的非神经元部位，并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疼痛是许多胃肠道疾病（例如肠易激综合症）的标志。它可能是由内脏器官的急性炎症引起的，也可能是先前受伤的残留物；其后果可能会使患者及其家人衰弱，并使治疗的临床医生感到沮丧。为了改善治疗选择并为许多顽固性内脏痛患者重燃希望，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标成功逆转慢性内脏痛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初始伤害地点较远、跨学科方法以及我们研究团队的多元化专业知识。