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

脊髓损伤(SCI)通常伴有额外的组织损伤(多发性创伤)， 激活疼痛(伤害性)纤维。如果这种伤害性输入驱动脊髓内位于或低于该位置的神经元， 在损伤部位，它会过度兴奋神经元，加剧细胞死亡，破坏长期恢复。这个 组织丢失的扩大(继发性损伤)与血脊髓屏障的破坏有关。 (BSCB)。初步数据显示，伤害性刺激增加了通道Sur1-Trpm4的表达 在构成BSCB的内皮细胞上发现。使用此通道可使过量的钠进入 导致癌细胞死亡，以及BSCB的破裂(毛细血管碎裂)。这种现象是 称为进行性出血坏死(PHN)。与此同时，血压也在上升 (高血压)刺激血液(出血)涌入脊髓，引发进一步的细胞死亡。 目的1将探讨伤害性刺激触发PHN的情况。这是假设的 在轻到中度损伤后不久就会观察到更大的PHN，在这两种情况下都会观察到这种影响 雄性和雌性大鼠，伤害性刺激的效果由学习(可控性)调节。这个 实验将使用细胞分析(Western Blotting)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。要浏览链接，请访问 还将监测高血压、血压和心率。 目标2将研究含有TRPV1受体的无髓鞘疼痛(C)纤维的作用，该受体是 加入了辣椒素。实验将测试这些纤维是否是必要的，是否足以诱导 脊髓损伤后的PHN和神经递质P物质的作用这些问题将通过化学方法解决 切断这些纤维，用辣椒素激活它们，然后向脊髓微量注射P物质。 目标3将探索伤害性输入如何触发Sur1-Trpm4的表达。有人建议阻止这一点 通道将减弱伤害性诱导的PHN，从而增强组织保护和长期恢复。 目的4评价血压变化对出血发生的影响。初步 数据显示，吻侧脊髓横断可阻断挫伤大鼠的伤害性高血压。 利用这一实验操作，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。后者将被使用药物治疗来操纵， 诱导或阻止这种效果。有研究表明，从药物上阻断血压升高将会 减轻伤害性出血及其对长期康复的不良影响。 这项工作的长期目标是减少脊髓损伤后继发性损伤的发展，从而 促进长期复苏。有人建议，阻断BSCB的崩溃或诱导伤害性反应 高血压会减少继发性损伤，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.