Chronic neuropathic pain, glial-immune responses and fetal alcohol exposure

慢性神经性疼痛、神经胶质免疫反应和胎儿酒精暴露

• 批准号: 8822147
• 负责人: ERIN Damita MILLIGAN
• 金额: $ 21.71万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822147
• 关键词: Adult; Adult Children; Afferent Neurons; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; B-Lymphocytes; Behavioral; Biodistribution; Biological Models; Blood; CCL2 gene; CXC Chemokines; Cells; Characteristics; Child; Chronic; Chronic Disease; Code; Cognitive; Cytokine Signaling; Development; Diabetes Mellitus; Disease; Disease susceptibility; Environment; Esthesia; Ethanol; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetus; Functional disorder; Future; Goals; Image; Immune; Immune System Diseases; Immune response; Immunologics; Individual; Inflammatory; Insulin; Integrins; Interleukin-10; Interleukins; Knowledge; Lead; Lesion; Leukocyte Trafficking; Leukocytes; Life; Light; Link; Lymphocyte Function-Associated Antigen-1; Maintenance; Mechanics; Mediating; Microglia; Molecular Profiling; Neuraxis; Neuroglia; Neuroimmunomodulation; Neurologic; Neurons; Neuropathy; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Outcome; Pain; Painless; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Phenotype; Physiological Adaptation; Play; Predisposition; Pregnancy; Process; Public Health; Rattus; Recruitment Activity; Rheumatoid Arthritis; Risk; Rodent Model; Role; Saccharin; Sciatic Neuropathy; Sensory; Sensory Ganglia; Signal Transduction; Signaling Molecule; Site; Source; Spinal; Spinal Cord; Spinal Ganglia; Spinal nerve structure; Stimulus; Synaptic plasticity; T-Lymphocyte; Tissue Harvesting; Touch sensation; Tumor Necrosis Factor-alpha; Work; alcohol exposure; allodynia; behavioral health; cell mediated immune response; cell type; chemokine; chronic neuropathic pain; cognitive function; cytokine; dosage; human TGFB1 protein; immune activation; immune function; in utero; insight; macrophage; migration; monocyte; nervous system disorder; neuropathology; novel; offspring; painful neuropathy; prenatal; prenatal exposure; public health relevance; response; satellite cell; signal processing; single photon emission computed tomography; trafficking

DESCRIPTION (provided by applicant): Chronic neuropathic pain, such as allodynia, defined as painful sensation to usually non-painful stimuli, is mediated by pathologically activated glial cells residing in both sensory dorsal root ganglia (DRG) and in the spinal cord. These cells secrete the pro-inflammatory factors, IL-1b and TNF-a, as well as chemokines, such as CCL2, that attract circulating leukocytes to the DRG and spinal cord regions. These leukocytes cross the blood-nerve and -spinal barriers, a process facilitated by the activation of the b-2 (b2)-integrin, lymphocyte function-associated antigen-1 (LFA-1), providing an additional source of IL-1b and TNF-a exacerbating neuronal pain signaling processes. Underlying factors that may predispose individuals to allodynia are generally not well recognized. Increasing evidence indicates that prenatal alcohol exposure (PAE) can produce long-lasting alterations to immune function and neuroimmune interactions, increasing the risk for a number of chronic immunologic disorders such as diabetes and rheumatoid arthritis. Specifically, PAE is thought to pathologically prime immune-like glial cells (satellite cells, astrocytes and microglia) disrupting their nutritive role in support of neuronal function during development and into adulthood. Whether PAE leads to heightened and enduring glial reactivity throughout adulthood leading to aberrant neuroimmune signaling is not well understood. The objective of this proposal is to examine whether moderate PAE can heighten allodynic responses in adult offspring using a well-established rodent model of chronic peripheral neuropathic pain, and by applying this model system, to understand underlying PAE-related aberrant neuroimmune interactions. Our overarching hypothesis states that: PAE produces chronic gliopathy and DRG and spinal leukocyte accumulation that mediate pathological pain in rats. The Specific Aims of the proposal are to: (1) identify the magnitude and role of DRG & spinal leukocyte accumulation in the development of neuropathic pain in adult PAE rats, and (2) identify the DRG and spinal cytokine/chemokine, glial activation and b2-integrin expression profile in PAE neuropathic rats. The studies could provide novel insights into whether an adverse in utero environment intersects with vulnerability to developing adult onset allodynia, as well identifying potential neuroimmune makers for discerning vulnerability to neuropathological pain, and more broadly, to disorders with an underlying neuroinflammatory component. These studies could also inform future studies targeting the development of interventional approaches for the amelioration of neuropathic pain in individuals predisposed to this chronic disabling neurologic disorder.

描述（由申请人提供）：慢性神经性疼痛，例如异常性疼痛，定义为对通常无痛性刺激的疼痛感，由存在于感觉背根神经节（DRG）和脊髓中的病理激活的神经胶质细胞介导。这些细胞分泌促炎因子 IL-1b 和 TNF-a 以及趋化因子（例如 CCL2），将循环白细胞吸引到 DRG 和脊髓区域。这些白细胞穿过血神经和脊髓屏障，b-2 (b2)-整合素、淋巴细胞功能相关抗原 1 (LFA-1) 的激活促进了这一过程，提供了 IL-1b 和 TNF-a 的额外来源，加剧了神经元疼痛信号传导过程。可能使个体易患异常性疼痛的潜在因素通常尚未得到充分认识。越来越多的证据表明，产前酒精暴露（PAE）会对免疫功能和神经免疫相互作用产生持久的改变，从而增加患糖尿病和类风湿关节炎等多种慢性免疫疾病的风险。具体来说，PAE 被认为在病理上引发免疫样神经胶质细胞（卫星细胞、星形胶质细胞和小胶质细胞）的破坏 它们在发育和成年期间支持神经元功能的营养作用。 PAE 是否会导致整个成年期的神经胶质反应性增强且持久，从而导致神经免疫信号异常，目前尚不清楚。本提案的目的是使用成熟的慢性周围神经病理性疼痛啮齿动物模型来检查中度 PAE 是否可以增强成年后代的异常性反应，并通过应用该模型系统来了解潜在的 PAE 相关的异常神经免疫相互作用。我们的总体假设指出：PAE 会产生慢性胶质病和 DRG 以及脊髓白细胞积聚，从而介导大鼠的病理性疼痛。该提案的具体目标是：(1) 确定成年 PAE 大鼠神经病理性疼痛发展中 DRG 和脊髓白细胞积累的程度和作用，以及 (2) 确定 PAE 神经病理性大鼠中的 DRG 和脊髓细胞因子/趋化因子、胶质细胞活化和 b2-整合素表达谱。这些研究可以提供新的见解，了解子宫内的不利环境是否与成人发病的异常性疼痛的脆弱性相交叉，并确定潜在的神经免疫因素，以识别神经病理性疼痛的脆弱性，更广泛地说，识别具有潜在神经炎症成分的疾病的脆弱性。这些研究还可以为未来的研究提供信息，这些研究旨在开发干预方法，以改善易患这种慢性致残性神经系统疾病的个体的神经病理性疼痛。