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

脊髓损伤（SCI）经常伴有额外的组织损伤（多发性创伤）， 激活疼痛（伤害感受）纤维。如果这种伤害性输入驱动脊髓内的神经元， 损伤部位，它可以过度兴奋神经元，促进细胞死亡，破坏长期恢复。的 组织缺损的扩大（继发性损伤）与血脊髓屏障的破坏有关 （BSCB）。初步数据显示，伤害性刺激增加了Sur 1-Trpm 4的表达， 在形成BSCB的内皮细胞上发现。参与这个通道允许过量的钠进入 细胞，诱导肿瘤细胞死亡，以及BSCB的破裂（毛细血管断裂）。这种现象 称为进行性出血性坏死（PHN）。与此同时，还有血压的上升 高血压导致大量血液涌入脊髓（出血），引发细胞进一步死亡。 目的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将观察到更大的PHN， 雄性和雌性大鼠，并且伤害性刺激的效果通过学习（可控性）来调节。的 实验将使用细胞分析（蛋白质印迹法）和免疫组织化学来探索这些细胞是如何被激活的。 变量影响出血的发展和受影响的细胞类型。探索与 高血压、血压和心率也将受到监测。 目的2将研究含有TRPV 1受体的无髓鞘疼痛（C）纤维的作用， 被辣椒素吸引实验将测试这些纤维是否是必要的和足够的诱导 SCI后PHN和神经递质物质P的作用。这些问题将通过化学方法解决。 损伤这些纤维，用辣椒素激活它们，然后将P物质显微注射到脊髓中。 目的3将探讨伤害性输入如何触发Sur 1-Trpm 4的表达。有人提议， 通道将减弱伤害性感受诱导的PHN，从而增强组织保护和长期恢复。 目的4评估血压变化如何影响出血的发展。初步 数据显示，在挫伤大鼠中，喙侧脊髓横切阻断了伤害感受诱导的高血压。 使用这种实验操作，所提出的实验将评估伤害性输入如何影响大脑皮层。 BSCB的完整性和高血压的影响。后者将使用药物治疗来操纵， 或阻止这种影响。这表明，阻断血压上升的药物将 减轻伤害性感觉诱发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， 促进长期复苏。有人提出，阻断BSCB的崩溃或伤害性感受诱导的 高血压可减少继发性损伤，促进康复。

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.