Modulating Pain Generators of Chronic Trigeminal Neuropathic Pain

调节慢性三叉神经病理性疼痛的疼痛发生器

基本信息

  • 批准号:
    10513813
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-01-01 至 2024-09-30
  • 项目状态:
    已结题

项目摘要

Veterans have more severe chronic pain than non-veteran patients and are reportedly twice as likely to die of an opioid overdose in attempts to find relief. These consequences lie behind the critical need to determine brain alterations causing chronification of pain that are too often progressing to the anxiety and depression responsible for the increased suicide rate among our veterans. Better understanding of underlying mechanisms driving chronic pain is imperative to development of more effective non-opioid treatment approaches for chronic pain. During the currently funded VA Merit grant period, we performed manganese enhanced MRI (MEMRI) studies using our experimental chronic neuropathic pain model. MEMRI allows visualization of neural activation in the small rodent brain using a 7T Bruker MRI scanner. As in clinical fMRI studies, we identified specific limbic emotional brain regions overactivated by chronic pain in addition to activation of the pain circuitry itself. It is apparent in our Preliminary Data histological follow-up that ongoing cellular stress is occurring in limbic brain circuitry. Due to the neuronal overactivation, pathophysiological alterations in limbic brain pain circuitry include increased expression of cellular stress biomarkers and altered expression of protective autophagy biomarkers. Autophagy is defined as the ongoing cellular protective mechanisms removing damaged and misfolded proteins generated during cellular stress. Disrupted autophagy homeostasis that produces autophagic dysfunction adversely affects cell function and eventually viability. The goal of the proposed studies is to examine whether boosting cell protective autophagy mechanisms can not only reduce neuropathic pain chronification related behaviors but can conceivably reduce the related brain pain circuitry neuropathology. Our studies performed at 8-10 weeks after induction in our chronic neuropathic pain model allows salient clinical relevance. We will test whether cellular stress/autophagy mechanisms are related to the noradrenergic alpha 1 receptor (NAα1R) signaling we identified as a primary chronic pain generator in the previous Merit grant funding period. The NAα1R blocker we will test is the clinical therapeutic doxazosin that might also be used as PTSD therapy. Doxazosin is longer lasting than the prazosin we tested in the same model in the previous grant period. Prazosin reduced chronic pain and aversive anxiety and depression related behaviors we observed through the 10 week time points (see Progress Report). We will test efficacy of doxazosin to reduce chronic neuropathic pain induced mechanical hypersensitivity, and perform anxiety and depression related behavioral assays. Comparisons of the efficacy of doxazosin can be made to prazosin and the effects of cellular stress inhibitors/autophagy enhancers. We find based on our recently completed MEMRI study that overactivation in specific limbic cortical regions after 10 weeks of ongoing neuropathic pain results in altered cellular stress/autophagy biomarker expression that accompanies the chronic pain related behaviors. The Aims proposed in this VA Merit renewal application include identification/validation of the cellular stress/autophagy RNA/protein expression signature in the chronic pain model at 10 weeks. Pilot efficacy testing of a cellular stress signaling pathway inhibitor and protective autophagy promotor finds reversal of chronic pain behaviors. Enhancement of protective autophagy mechanisms as defense against cellular stress and disrupted cellular homeostasis will be further demonstrated by quantifying oxidative stress/autophagy RNA, proteins, and other neuropathology as readouts. Imaging the distribution of inflammatory biomarker cathepsin B over time in live animals with whole body IVIS fluorescent infrared imaging will be a readout of the inflammatory component in peripheral and central nervous system. Completion of our assessment of the efficacy of these treatments to provide enhancement of protective autophagy mechanisms during chronic pain as defense against cellular stress and chronic pain related behaviors will increase the understanding of the chronification of neuropathic pain. Improved understanding will lead to better non-opioid treatments for chronic pain that provide better outcomes for veterans living with chronic pain.
退伍军人比非退伍军人患者有更严重的慢性疼痛,据报道, 过量服用阿片类药物以寻求缓解这些后果背后的关键需要,以确定大脑 导致疼痛慢性化的改变,这些改变往往进展为焦虑和抑郁, 导致退伍军人自杀率上升更好地理解驱动的基本机制 慢性疼痛对于开发更有效的慢性疼痛的非阿片样物质治疗方法是必要的。 在目前资助的VA优异奖期间,我们进行了锰增强MRI(MEMRI)研究 使用我们的实验性慢性神经性疼痛模型。MEMRI允许可视化的神经激活, 使用7 T Bruker MRI扫描仪测量小啮齿动物大脑。在临床功能磁共振成像研究中,我们确定了特定的边缘系统, 除了疼痛回路本身的激活之外,慢性疼痛也会过度激活大脑的情感区域。是 在我们的初步数据组织学随访中,明显的是边缘脑中正在发生的细胞应激 电路由于神经元过度激活,边缘脑疼痛回路的病理生理学改变包括 细胞应激生物标志物的表达增加和保护性自噬生物标志物的表达改变。 自噬是细胞清除受损和错误折叠蛋白质的一种持续的细胞保护机制 在细胞压力下产生。自噬稳态被破坏,导致自噬功能障碍 不利地影响细胞功能并最终影响存活力。拟议研究的目标是审查是否 增强细胞保护性自噬机制不仅可以减少神经病理性疼痛慢性化相关 行为,但可以想象减少相关的大脑疼痛回路神经病理学。我们的研究在 8-10在我们的慢性神经病理性疼痛模型中,诱导后20周允许显著的临床相关性。 我们将测试细胞应激/自噬机制是否与去甲肾上腺素能α 1受体有关 (NAα 1 R)信号传导,我们确定为主要的慢性疼痛发生器在以前的优异奖资助期间。 我们将测试的NAα 1 R阻断剂是临床治疗性多沙唑嗪,也可用作PTSD治疗。 多沙唑嗪比我们在前一个资助期在同一模型中测试的哌唑嗪持续时间更长。哌唑嗪 减少慢性疼痛和厌恶性焦虑和抑郁相关的行为,我们观察到通过10周 时间点(见进度报告)。我们将测试多沙唑嗪减少慢性神经性疼痛诱导的疗效 机械超敏反应,并进行焦虑和抑郁相关的行为测定。的比较 多沙唑嗪的功效可以与哌唑嗪和细胞应激抑制剂/自噬增强剂的效果相同。 我们发现,根据我们最近完成的MEMRI研究,在特定的边缘皮层区域过度激活后, 持续10周的神经性疼痛导致细胞应激/自噬生物标志物表达改变, 伴随着慢性疼痛相关的行为。在此VA Merit更新申请中提出的目标包括 慢性疼痛中细胞应激/自噬RNA/蛋白质表达特征的鉴定/验证 模型10周细胞应激信号通路抑制剂和保护性自噬的初步功效测试 促进者发现慢性疼痛行为的逆转。保护性自噬机制的增强, 对细胞应激和细胞稳态破坏的防御将通过定量分析进一步证明。 氧化应激/自噬RNA、蛋白质和其他神经病理学作为读数。成像的分布 用全身IVIS荧光红外成像在活体动物中随时间推移炎性生物标志物组织蛋白酶B 将是外周和中枢神经系统中炎症成分的读数。 完成我们对这些治疗有效性的评估, 慢性疼痛中的自噬机制作为对细胞应激和慢性疼痛相关行为的防御 将增加对神经性疼痛慢性化的理解。更好的理解将导致 更好的非阿片类药物治疗慢性疼痛,为患有慢性疼痛的退伍军人提供更好的结果。

项目成果

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KARIN N. WESTLUND-HIGH其他文献

KARIN N. WESTLUND-HIGH的其他文献

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{{ truncateString('KARIN N. WESTLUND-HIGH', 18)}}的其他基金

Advancing Development of Novel Immunotherapy for Chemotherapy-induced Peripheral Neuropathy (CIPN)
推进化疗引起的周围神经病变 (CIPN) 的新型免疫疗法的发展
  • 批准号:
    10588384
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
ShEEP Request for Biotek Cytation 5 Imaging System
ShEEP 请求 Biotek Cytation 5 成像系统
  • 批准号:
    10175798
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Peripheral and Central Pain Generators of Chronic Trigeminal Neuropathic Pain
慢性三叉神经病理性疼痛的周围和中枢疼痛发生器
  • 批准号:
    9031396
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Modulating Pain Generators of Chronic Trigeminal Neuropathic Pain
调节慢性三叉神经病理性疼痛的疼痛发生器
  • 批准号:
    10293538
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Modulating Pain Generators of Chronic Trigeminal Neuropathic Pain
调节慢性三叉神经病理性疼痛的疼痛发生器
  • 批准号:
    10012520
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Physiological and Emotional Reactivity to Pain after Physical and Sexual Abuse
身体和性虐待后对疼痛的生理和情感反应
  • 批准号:
    8214456
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Glutamate Induced Molecular Events Contributing to Chro*
谷氨酸诱导的分子事件有助于 Chro*
  • 批准号:
    6533040
  • 财政年份:
    2001
  • 资助金额:
    --
  • 项目类别:
Glutamate Induced Molecular Events
谷氨酸诱导的分子事件
  • 批准号:
    6440349
  • 财政年份:
    2001
  • 资助金额:
    --
  • 项目类别:
Neurogeneic Amplification of Pancreatitis Pain
胰腺炎疼痛的神经源性放大
  • 批准号:
    7871859
  • 财政年份:
    2000
  • 资助金额:
    --
  • 项目类别:
Neurogenic Amplification of Pancreatitis Pain
胰腺炎疼痛的神经源性放大
  • 批准号:
    8288067
  • 财政年份:
    2000
  • 资助金额:
    --
  • 项目类别:

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Selective actin remodeling of sensory neurons for acute pain management
感觉神经元的选择性肌动蛋白重塑用于急性疼痛管理
  • 批准号:
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  • 财政年份:
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    10783106
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Development of A Focused Ultrasound Device for Noninvasive, Peripheral Nerve Blockade to Manage Acute Pain
开发用于非侵入性周围神经阻断来治疗急性疼痛的聚焦超声装置
  • 批准号:
    10740796
  • 财政年份:
    2023
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Predicting Pediatric Sickle Cell Disease Acute Pain Using Mathematical Models Based on mHealth Data
使用基于移动健康数据的数学模型预测儿童镰状细胞病急性疼痛
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Non-Contingent Acute Pain Stress Drives Analgesic Protection in Rats.
非偶然急性疼痛应激驱动大鼠镇痛保护。
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    575854-2022
  • 财政年份:
    2022
  • 资助金额:
    --
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    Alexander Graham Bell Canada Graduate Scholarships - Master's
Prefrontal Cortex Hemodynamic Responses to Mindfulness Meditation and Acute Pain
前额皮质血流动力学对正念冥想和急性疼痛的反应
  • 批准号:
    467076
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    Studentship Programs
A Multimodal Approach for Monitoring Prolonged Acute Pain in Neonates
监测新生儿长期急性疼痛的多模式方法
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