Effect of inflammation on recovery and pain after spinal cord injury

炎症对脊髓损伤后恢复和疼痛的影响

• 批准号: 9212209
• 负责人: James William Grau
• 金额: $ 18.24万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212209
• 关键词: Acute; Adenosine; Adverse effects; Affect; Afferent Neurons; Affinity; Apoptosis; Apoptotic; Astrocytes; Attenuated; Behavioral; Binding Sites; Biomedical Research; CASP1 gene; CASP3 gene; CASP8 gene; Calcium; Capsaicin; Cell Death; Cell Separation; Cells; Chemicals; Chest; Collaborations; Contusions; Coupled; Cytolysis; Data; Development; Drug Combinations; Environment; Event; Extracellular Fluid; Feedback; Fiber; Fostering; Goals; Immunohistochemistry; Impairment; Inflammasome; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-1 beta; Interleukin-18; Interruption; Ion Channel; Irritants; Lead; Locomotor Recovery; Mediating; Methods; Microglia; Modeling; Molecular Profiling; Multiprotein Complexes; Neuroglia; Neurons; Nociception; Pain; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Probenecid; Procedures; Process; Purinoceptor; RNA Interference; Rattus; Recovery; Regimen; Regulation; Research; Research Personnel; Rodent; Role; Secondary to; Shock; Signal Transduction; Site; Spinal; Spinal Cord Plasticity; Spinal Injuries; Spinal cord injury; Stretching; System; TNF gene; TRPV1 gene; Tactile; Techniques; Testing; Texas; Time; Tissues; Translating; Western Blotting; Withdrawal; Work; allodynia; cell type; central sensitization; chronic pain; clinical practice; cytokine; ds-DNA; effective therapy; extracellular; indexing; inhibitor/antagonist; injured; innovation; nerve injury; novel; protective effect; protein profiling; public health relevance; receptor; relating to nervous system; research facility; response; success; tripolyphosphate

 DESCRIPTION (provided by applicant): The tissue damage caused by a spinal cord injury (SCI) breaks down cellular barriers and alters the composition of the extracellular fluid, initiatig a chemical wave that impacts uninjured cells in the surrounding region, inducing a state that primes the cells to die through a form of pro-inflammatory programmed cell death (pyroptosis). In addition, damage to descending pathways disrupts the regulation of lower (caudal) spinal systems, allowing afferent signals to induce a state of neural over-excitation (central sensitization) that can foster chronic pain and promote cell death. Supporting this, research has shown that pain (nociceptive) input soon after SCI enhances tissue loss, undermines behavioral function, and promotes the development of chronic pain. It is hypothesized that nociceptive stimulation undermines recovery after SCI because it promotes the induction of pyroptosis and thereby enhances secondary tissue damage. Pyroptosis is mediated by a multi-protein complex called the inflammasome, which initiates the proteolytic cleavage of pro-caspase-1 to form caspase 1. Caspase 1 engages cellular signals that cause the release of pro- inflammatory cytokines (e.g., interleukin 1-ß [IL-1ß] and tumor necrosis factor [TNF]). Activation of the inflammasome is tied to a membrane channel (pannexin-1) and the adjoining P2X7 receptor (P2X7R). When engaged, the pannexin-1 channel allows IL-1ß and TNF to flow out of the cell. Calcium entry through the pannexin-1 channel initiates intracellular processes that lead to cell death through lysis. The current project will evaluate whether nociceptive input engages these processes and thereby leads to greater cell loss. A rodent (rat) model will be used. Subjects will receive a thoracic contusion injury. Prior work has shown that the application of a peripheral irritant (capsaicin) undermines behavioral recovery and enhances pain reactivity to tactile stimulation (allodynia). Aim 1 will establish the circumstances under which this occurs and assess tissue damage. It is hypothesized that spinal systems are especially vulnerable during the first few days after injury. Preliminary data indicate that nociceptive stimulation engages cellular signals indicative of pyroptosis (caspase 1, IL-1ß, IL-18). Aim 2 will examine how these processes unfold over time and the cell types affected. It is proposed that the spread of pyroptosis can be halted by a drug combination (probenecid plus Brilliant Blue-G [BBG]) that inhibits both the pannexin-1 channel and the P2X7R. Aim 3 will verify that this drug treatment attenuates the induction of pyroptosis in the acute stage. We also predict that it will reduce behavioral and cellular signs of central sensitization. After an effective regimen is derived, we will test whether it has a protective effect that blocks the adverse effect of nociceptive stimulation on long-term recovery. By discovering treatments that reduce cell loss after SCI, we hope to promote recovery. Further, because activation of the pannexin-1 channel can contribute to the development of central sensitization, interrupting this process should reduce chronic pain after injury.

 描述（由申请人提供）：脊髓损伤（SCI）引起的组织损伤破坏细胞屏障并改变细胞外液的组成，引发化学波，影响周围区域的未受伤细胞，诱导一种状态，通过促炎性程序性细胞死亡（焦亡）的形式引发细胞死亡。此外，下行通路的损伤破坏了较低（尾部）脊髓系统的调节，使传入信号诱导神经过度兴奋（中枢致敏）状态，这可能会促进慢性疼痛并促进细胞死亡。支持这一点，研究表明，疼痛（伤害性）输入后不久，SCI增强组织损失，破坏行为功能，并促进慢性疼痛的发展。据推测，伤害性刺激破坏了SCI后的恢复，因为它促进了焦亡的诱导，从而增强了继发性组织损伤。 焦亡由称为炎性体的多蛋白复合物介导，其启动胱天蛋白酶原-1的蛋白水解裂解以形成胱天蛋白酶1。胱天蛋白酶1参与引起促炎细胞因子释放的细胞信号（例如，白细胞介素1-β [IL-1 β]和肿瘤坏死因子[TNF]）。炎性小体的激活与膜通道（泛连接蛋白-1）和相邻的P2 X7受体（P2 X7 R）有关。当参与时，泛连接蛋白-1通道允许IL-1 β和TNF流出细胞。钙通过泛连接蛋白-1通道进入启动细胞内过程，导致细胞通过裂解死亡。目前的项目将评估伤害性输入是否参与这些过程，从而导致更大的细胞损失。 将使用啮齿动物（大鼠）模型。受试者将 胸部挫伤先前的研究表明，外周刺激物（辣椒素）的应用破坏了行为恢复，并增强了对触觉刺激的疼痛反应（异常性疼痛）。目标1将确定发生这种情况的情况并评估组织损伤。据推测，脊柱系统在受伤后的最初几天特别脆弱。初步数据表明，伤害性刺激涉及指示焦亡的细胞信号（半胱天冬酶1、IL-1 β、IL-18）。目标2将研究这些过程如何随着时间的推移和受影响的细胞类型展开。有人提出，可以通过抑制泛连接蛋白-1通道和P2 X7 R的药物组合（丙磺舒加亮蓝-G [BBG]）来阻止焦亡的传播。目的3将验证这种药物治疗减弱急性期的焦睑下垂诱导。我们还预测，它将减少中枢致敏的行为和细胞迹象。在得出有效的方案后，我们将测试它是否具有保护作用，可以阻止伤害性刺激对长期恢复的不利影响。 通过发现减少SCI后细胞损失的治疗方法，我们希望促进恢复。此外，由于泛连接蛋白-1通道的激活可以促进中枢致敏的发展，因此中断这一过程可以减少损伤后的慢性疼痛。

项目成果

Pain Input After Spinal Cord Injury (SCI) Undermines Long-Term Recovery and Engages Signal Pathways That Promote Cell Death.

• DOI: 10.3389/fnsys.2018.00027
• 发表时间: 2018
• 期刊: Frontiers in systems neuroscience
• 影响因子: 3
• 作者: Turtle JD;Strain MM;Reynolds JA;Huang YJ;Lee KH;Henwood MK;Garraway SM;Grau JW
• 通讯作者: Grau JW