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) 经常伴有额外的组织损伤（多发伤）， 激活疼痛（伤害性）纤维。如果这种伤害性输入驱动脊髓内的神经元， 在受伤部位，它会过度兴奋神经元，加速细胞死亡，并破坏长期恢复。这 组织损失的扩大（继发性损伤）与血液脊髓屏障的破坏有关 （BSCB）。初步数据表明，伤害性刺激会增加 Sur1-Trpm4 的表达，这是一个通道 发现于形成 BSCB 的内皮细胞上。参与该通道允许过量的钠进入 细胞，诱导胶体细胞死亡和 BSCB 破裂（毛细血管破裂）。这种现象是 称为进行性出血性坏死（PHN）。同时，血压也会升高 （高血压）会导致大量血液（出血）流入脊髓，引发进一步的细胞死亡。 目标 1 将探讨伤害性刺激触发 PHN 的情况。据推测 在轻度至中度损伤后不久就会观察到更大的 PHN，在两种情况下都会观察到这种影响 雄性和雌性大鼠，并且伤害性刺激的效果是通过学习（可控性）调节的。这 实验将使用细胞测定（蛋白质印迹）和免疫组织化学来探索这些 变量影响出血的发展和受影响的细胞类型。要探索链接 高血压、血压和心率也将受到监测。 目标 2 将检查含有 TRPV1 受体的无髓鞘疼痛 (C) 纤维的作用，该受体是 被辣椒素所吸引。实验将测试这些纤维是否必要且足以诱导 SCI 后的 PHN 以及神经递质物质 P 的作用。这些问题将通过化学方法解决 损伤这些纤维，使用辣椒素激活它们，并将 P 物质显微注射到脊髓中。 目标 3 将探讨伤害性输入如何触发 Sur1-Trpm4 表达。建议屏蔽此 通道将减弱伤害感受引起的 PHN，从而增强组织保护和长期恢复。 目标 4 评估血压变化如何影响出血的发生。初步的 数据显示，头端脊髓横断可以阻止挫伤大鼠中伤害感受诱发的高血压。 使用这种实验操作，拟议的实验将评估伤害性输入如何影响 BSCB 的完整性和高血压的影响。后者将通过药物治疗来控制 诱导或阻止这种效应。建议通过药物阻断血压升高 减轻伤害感受引起的出血及其对长期恢复的不利影响。 这项工作的长期目标是减少 SCI 后继发性损伤的发生，从而 促进长期康复。建议阻断 BSCB 的崩溃或伤害感受引起的 高血压会减少继发性损伤，促进康复。