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: 10455530
• 负责人: James William Grau
• 金额: $ 28.52万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455530
• 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; blood pressure elevation; 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（多发损伤）

项目成果

Engaging pain fibers after a spinal cord injury fosters hemorrhage and expands the area of secondary injury.

• DOI: 10.1016/j.expneurol.2018.09.018
• 发表时间: 2019-01
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Turtle JD;Henwood MK;Strain MM;Huang YJ;Miranda RC;Grau JW
• 通讯作者: Grau JW

Contribution of Brain Processes to Tissue Loss After Spinal Cord Injury: Does a Pain-Induced Rise in Blood Pressure Fuel Hemorrhage?

• DOI: 10.3389/fnsys.2021.733056
• 发表时间: 2021
• 期刊: Frontiers in systems neuroscience
• 影响因子: 3
• 作者: Fauss GNK;Strain MM;Huang YJ;Reynolds JA;Davis JA;Henwood MK;West CR;Grau JW
• 通讯作者: Grau JW

Noxious Stimulation Induces Acute Hemorrhage and Impairs Long-Term Recovery after Spinal Cord Injury (SCI) in Female Rats: Evidence Estrous Cycle May Have a Modulatory Effect.

• DOI: 10.1089/neur.2021.0055
• 发表时间: 2022
• 期刊: Neurotrauma reports
• 影响因子: 2.4
• 作者: Baine RE;Johnston DT;Strain MM;Henwood MK;Davis JA;Reynolds JA;Giles ED;Grau JW
• 通讯作者: Grau JW

Behavioral studies of spinal conditioning: The spinal cord is smarter than you think it is.

• DOI: 10.1037/xan0000332
• 发表时间: 2022-10
• 期刊: JOURNAL OF EXPERIMENTAL PSYCHOLOGY-ANIMAL LEARNING AND COGNITION
• 影响因子: 1.3
• 作者: Grau, James W.;Hudson, Kelsey E.;Tarbet, Megan M.;Strain, Misty M.
• 通讯作者: Strain, Misty M.

Brain-Dependent Processes Fuel Pain-Induced Hemorrhage After Spinal Cord Injury.

大脑依赖性过程会加剧脊髓损伤后疼痛引起的出血。

• DOI: 10.3389/fnsys.2019.00044
• 发表时间: 2019
• 期刊: Frontiers in systems neuroscience
• 影响因子: 3
• 作者: Reynolds,JoshuaA;Henwood,MelissaK;Turtle,JoelD;Baine,RachelE;Johnston,DavidT;Grau,JamesW
• 通讯作者: Grau,JamesW