Nociceptive input after spinal cord injury (SCI) expands the region of secondary injury and undermines long-term recovery

脊髓损伤（SCI）后的伤害性输入会扩大继发性损伤的区域并破坏长期恢复

• 批准号: 10213852
• 负责人: James William Grau
• 金额: $ 28.55万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213852
• 关键词: Address; Adverse effects; Affect; Attention; Attenuated; Automobile Driving; Axon; Blinded; Blood; Blood Pressure; Blood capillaries; Brain; C Fiber; Capsaicin; Cardiovascular Physiology; Categories; Cell Death; Cell physiology; Cells; Cellular Assay; Chemicals; Clinical; Contusions; Data; Development; Drug usage; Endothelial Cells; Erythrocytes; Experimental Designs; Female; Fiber; Fostering; Goals; Heart Rate; Hemorrhage; Histologic; Hour; Hypertension; Immune response; Immunohistochemistry; Impairment; Individual; Infiltration; Injury; Learning; Lesion; Light; Link; Mediating; Monitor; Multiple Trauma; Necrosis; Neurons; Neurotransmitters; Nociception; Oligodendroglia; Pain; Pharmacology; Pharmacotherapy; Process; Rattus; Recovery; Research Personnel; Role; Sensory; Signal Transduction; Site; Sodium; Source; Spinal; Spinal Cord; Spinal Cord transection injury; Spinal cord injury; Substance P; TRPV1 gene; Techniques; Testing; Time; Tissue Expansion; Tissues; Translating; Up-Regulation; Western Blotting; Work; cell type; clinical practice; cytokine; experience; experimental study; injured; innovation; male; pain signal; receptor; spinal cord injury pain; white matter

Spinal cord injuries (SCI) are frequently accompanied by additional tissue damage (polytrauma) that activates pain (nociceptive) fibers. If this nociceptive input drives neurons within the spinal cord at, or below, the site of injury, it can over-excite neurons, enhance cell death, and undermine long-term recovery. The expansion of tissue loss (secondary injury) has been related to a disruption in the blood spinal cord barrier (BSCB). Preliminary data show that nociceptive stimulation increases the expression of Sur1-Trpm4, a channel found on the endothelial cells that form the BSCB. Engaging this channel allows excessive sodium to enter the cell, inducing oncotic cell death, and a breakdown (capillary fragmentation) of the BSCB. This phenomenon is known as progressive hemorrhage necrosis (PHN). At the same time, there is a rise in blood pressure (hypertension) that fuels a surge of blood (hemorrhage) into the spinal cord, triggering further cell death. Aim 1 will explore the circumstances under which nociceptive stimulation triggers PHN. It is hypothesized that greater PHN will be observed soon after a light to moderate injury, that the effect will be observed in both male and female rats, and that the effect of nociceptive stimulation is regulated by learning (controllability). The experiments will use cellular assays (Western blotting) and immunohistochemistry to explore how these variables influence the development of hemorrhage and the cell types affected. To explore the link to hypertension, blood pressure and heart rate will also be monitored. Aim 2 will examine the role of unmyelinated pain (C) fibers that contain the TRPV1 receptor, which is engaged by capsaicin. The experiments will test whether these fibers are necessary and sufficient to induce PHN after SCI and the role of the neurotransmitter substance P. These issues will be addressed by chemically lesioning these fibers, activating them using capsaicin, and microinjecting substance P into the spinal cord. Aim 3 will explore how nociceptive input triggers Sur1-Trpm4 expression. It is proposed that blocking this channel will attenuate nociception-induced PHN and thereby enhance tissue sparing and long-term recovery. Aim 4 evaluates how changes in blood pressure influence the development of hemorrhage. Preliminary data show that a rostral spinal cord transection blocks nociception-induced hypertension in contused rats. Using this experimental manipulation, the proposed experiments will evaluate how nociceptive input affects the integrity of the BSCB and the effect of hypertension. The latter will be manipulated using drug treatments that induce, or block, this effect. It is suggested that pharmacologically blocking the rise in blood pressure will attenuate nociception-induced hemorrhage and its adverse effect on long-term recovery. The long-term goal of this work is to reduce the development of secondary injury after SCI and thereby foster long-term recovery. It is proposed that blocking the breakdown of the BSCB or nociception-induced hypertension will reduce secondary injury and promote recovery.

脊髓损伤（SCI）经常伴随着其他组织损伤（Polytrauma） 激活疼痛（伤害感受）纤维。如果这种伤害感受的输入将神经元驱动在脊髓或以下的脊髓内 损伤部位，它可以过度示意性神经元，增强细胞死亡并破坏长期恢复。这 组织损失的扩展（继发损伤）与血脊髓屏障的破坏有关 （BSCB）。初步数据表明，伤害性刺激增加了SUR1-TRPM4的表达， 在形成BSCB的内皮细胞上发现。参与此通道允许过多的钠进入 细胞，诱导肿瘤细胞死亡以及BSCB的分解（毛细血管碎片）。这种现象是 被称为进行性出血坏死（PHN）。同时，血压升高 （高血压）将血液（出血）激增到脊髓中，引发进一步的细胞死亡。 AIM 1将探索伤害感受刺激触发PHN的情况。它是假设的 在轻伤到中度受伤后将很快观察到更大的PHN 雄性和雌性大鼠，并且受到学习（可控性）调节伤害感受刺激的作用。这 实验将使用细胞测定（蛋白质印迹）和免疫组织化学来探讨这些 变量会影响出血的发展和受影响的细胞类型。探索链接 高血压，血压和心率也将受到监测。 AIM 2将检查包含TRPV1受体的无髓疼痛（C）纤维的作用， 由辣椒素参与。实验将测试这些纤维是否需要且足以诱导 SCI之后的PHN和神经递质物质的作用。这些问题将通过化学解决 将这些纤维病变，使用辣椒素激活它们，并将其显微注射物质p进入脊髓。 AIM 3将探讨伤害感受输入触发器SUR1-TRPM4表达。有人提出阻止这个 通道将减弱伤害感受吸引诱导的PHN，从而增强组织的保留和长期恢复。 AIM 4评估血压变化如何影响出血的发展。初步的 数据表明，鼻脊髓横断会阻止伤害感受诱导的挫伤大鼠的高血压。 使用这种实验操作，提出的实验将评估伤害感受的输入如何影响 BSCB的完整性和高血压的影响。后者将使用药物治疗来操纵 诱导或阻止这种效果。建议在药理上阻止血压升高 减弱伤害感受诱导的出血及其对长期恢复的不良影响。 这项工作的长期目标是减少SCI之后的继发伤害的发展，从而减少 促进长期恢复。有人提出阻止BSCB或伤害感受诱导的崩溃 高血压将减少继发性伤害并促进康复。