The glymphatic system at the crossroad of integrative health approaches inchronic pain

处于综合健康十字路口的类淋巴系统接近慢性疼痛

基本信息

  • 批准号:
    10626911
  • 负责人:
  • 金额:
    $ 54.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

Abstract: The glymphatic system is a network of perivascular spaces that function as a waste clearance system, analogous to the peripheral lymphatic system. Reduced glymphatic function has been a hallmark observation in aging as well as models of Alzheimer's disease, diabetes, hypertension, traumatic brain injury, excess alcohol intake, and chronic unpredictable stress. Preliminary data shows that acute and chronic pain, and one night of light all suppressed glymphatic function. This application will use the murine sparse nerve injury (SNI) model to understand how the brain responds to chronic neuropathic pain. Sleep complaints are prevalent in chronic pain patients, and chronic sleep restriction increases pain sensitivity in mice. Norepinephrine (NE), which disrupts sleep and is released in stressful conditions, suppresses glymphatic function. We hypothesize that increase NE levels in SNI reduce glymphatic function, triggering cytokine accumulation, neuronal excitability, sleep disruption and pain sensitization in a feedforward loop (Aim 1). Traditional analgesics have been shown to relieve pain in models of chronic pain. Our preliminary data show that the same agents restore glymphatic function in SNI mice with no effect on glymphatic functions in control mice. We hypothesize that reducing the severity of pain via analgesia improves glymphatic function by reducing NE levels, which in turn reduces cytokine accumulation and excitability and improves sleep quality (Aim 2.1). Yet, efficacy of modern pharmacology is variable in the patient population, suggesting that while modulation of neural pathways is partially effective, pathology remains. We hypothesize that neuropathic pain induces a CNS maladaptive response involving reduced glymphatic flow, inflammation and waste accumulation. Because both natural and mind-body interventions target multiple facets of glymphatic disruption (sleep, inflammation, cardiovascular disease), we hypothesize that natural supplements (melatonin and eicosapentaenoic acid (an ω-3 fatty acid)) and mind-body interventions (voluntary exercise, improved sleep, and acupuncture) will improve glymphatic disruption in chronic pain (Aims 2.2 and 2.3). The timing of treatment is critical, because the circadian system is integrated into every process in the body including the glymphatic system, the immune system, and chronic pain. We propose that targeting therapeutics to reinforce the rhythm in glymphatic function and clearance will optimize the effect of treatment which can be quantified as an additional decrease in cytokine accumulation and hyperalgesia in SNI (Aim 3). We will time sleep improvements via increased temperature, voluntary exercise, melatonin, and acupuncture, to the endogenous rhythm of CSF distribution - high glymphatic clearance during rest, and low during wakefulness. Aim 3 is unique in that it tests whether efficacy of mind-body therapies, in improving glymphatic function and reducing pain sensitivity, can change based on when during the day they are administered. Overall, this application aims to define whether glymphatic activity may serve as a target for complementary therapeutic approaches and also as a biomarker establishing the efficacy of treatment.
摘要:淋巴系统是血管周围空间的网络,起着排泄物清除系统的作用, 类似于外周淋巴系统。淋巴功能降低一直是 衰老以及阿尔茨海默病、糖尿病、高血压、创伤性脑损伤、过量饮酒的模型 摄入量和慢性不可预知的压力。初步数据显示,急性和慢性疼痛,以及一晚 光都抑制了淋巴功能。此应用程序将使用小鼠稀疏神经损伤(SNI)模型来 了解大脑对慢性神经病理性疼痛的反应。睡眠主诉在慢性疼痛中很常见 长期睡眠限制会增加小鼠对疼痛的敏感性。去甲肾上腺素(NE),它破坏 睡眠,在压力大的情况下被释放,抑制淋巴功能。我们假设增加东北方向 SNI水平降低淋巴功能,触发细胞因子堆积,神经元兴奋性,睡眠中断 以及前馈环路中的痛敏作用(目标1)。传统的止痛药已经被证明可以缓解疼痛。 慢性疼痛的模型。我们的初步数据显示,相同的药物可以恢复SNI小鼠的淋巴功能 对对照组小鼠的淋巴功能无影响。我们假设通过减少疼痛的严重程度 止痛通过降低去甲肾上腺素水平来改善淋巴功能,去甲肾上腺素进而减少细胞因子的积聚和 提高兴奋性和改善睡眠质量(目标2.1)。然而,现代药理学在患者身上的疗效是不同的。 这表明,尽管神经通路的调节部分有效,但病理学仍然存在。我们 假设神经病理性疼痛导致中枢神经系统适应不良反应,包括淋巴流量减少, 发炎和废物堆积。因为自然干预和身心干预都针对多个方面 对于生殖器功能紊乱(睡眠、炎症、心血管疾病),我们假设天然补充剂 (褪黑素和二十碳五烯酸(一种ω-3脂肪酸))和心身干预(自愿锻炼, 改善睡眠和针灸)将改善慢性疼痛的淋巴干扰(目标2.2和2.3)。这个 治疗的时机是至关重要的,因为生理系统被整合到体内的每一个过程中,包括 淋巴系统、免疫系统和慢性疼痛。我们建议通过靶向治疗来加强 淋巴功能和清除的节律将优化治疗效果,这可以量化为 SNI中细胞因子积聚和痛觉过敏的额外减少(目标3)。我们会计时入睡 通过升高体温、自愿锻炼、褪黑激素和针灸来改善内源性 脑脊液分布节律--休息时淋巴清除率高,清醒时低。Aim 3是独一无二的 因为它测试了心身疗法在改善淋巴功能和减轻疼痛方面的有效性 敏感度可以根据一天中使用它们的时间而变化。总的来说,这个应用程序的目标是 确定淋巴活动是否可以作为补充治疗方法的靶点,也可以作为 确定治疗效果的生物标记物。

项目成果

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Maiken Nedergaard其他文献

Maiken Nedergaard的其他文献

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{{ truncateString('Maiken Nedergaard', 18)}}的其他基金

Administrative Core
行政核心
  • 批准号:
    10673148
  • 财政年份:
    2022
  • 资助金额:
    $ 54.98万
  • 项目类别:
Project 2: Periarterial CSF pumping: Dependence on state of brain activity
项目 2:动脉周围脑脊液泵送:取决于大脑活动状态
  • 批准号:
    10673161
  • 财政年份:
    2022
  • 资助金额:
    $ 54.98万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10516498
  • 财政年份:
    2022
  • 资助金额:
    $ 54.98万
  • 项目类别:
Project 2: Periarterial CSF pumping: Dependence on state of brain activity
项目 2:动脉周围脑脊液泵送:取决于大脑活动状态
  • 批准号:
    10516502
  • 财政年份:
    2022
  • 资助金额:
    $ 54.98万
  • 项目类别:
Does suppression of glymphatic flow explain why chronic neuropathic pain elevates the risk of developing Alzheimer-like dementia?
类淋巴液流的抑制是否可以解释为什么慢性神经性疼痛会增加患阿尔茨海默样痴呆的风险?
  • 批准号:
    10711478
  • 财政年份:
    2021
  • 资助金额:
    $ 54.98万
  • 项目类别:
Does suppression of glymphatic flow explain why chronic neuropathic pain elevates the risk of developing Alzheimer-like dementia?
类淋巴液流的抑制是否可以解释为什么慢性神经性疼痛会增加患阿尔茨海默样痴呆的风险?
  • 批准号:
    10834414
  • 财政年份:
    2021
  • 资助金额:
    $ 54.98万
  • 项目类别:
The glymphatic system at the crossroad of integrative health approaches inchronic pain
处于综合健康十字路口的类淋巴系统接近慢性疼痛
  • 批准号:
    10213385
  • 财政年份:
    2021
  • 资助金额:
    $ 54.98万
  • 项目类别:
The glymphatic system at the crossroad of integrative health approaches inchronic pain
处于综合健康十字路口的类淋巴系统接近慢性疼痛
  • 批准号:
    10453615
  • 财政年份:
    2021
  • 资助金额:
    $ 54.98万
  • 项目类别:
Para-Vascular Basis of Small Vessel Disease
小血管疾病的血管旁基础
  • 批准号:
    9263196
  • 财政年份:
    2016
  • 资助金额:
    $ 54.98万
  • 项目类别:
Para-Vascular Basis of Small Vessel Disease
小血管疾病的血管旁基础
  • 批准号:
    9756479
  • 财政年份:
    2016
  • 资助金额:
    $ 54.98万
  • 项目类别:

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针灸治疗血液透析患者疲劳——自主神经系统双盲RCT研究。
  • 批准号:
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  • 财政年份:
    2017
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支持针灸治疗心理社会方面的基于大脑的机制的优化——一项超扫描功能磁共振成像研究
  • 批准号:
    9999445
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    2016
  • 资助金额:
    $ 54.98万
  • 项目类别:
Optimization of brain-based mechanisms supporting psychosocial aspects of acupuncture therapy - a hyperscanning fMRI study
支持针灸治疗心理社会方面的基于大脑的机制的优化——一项超扫描功能磁共振成像研究
  • 批准号:
    9348587
  • 财政年份:
    2016
  • 资助金额:
    $ 54.98万
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Establishment of prevention method for sarcopenia in elderly by acupuncture therapy
针灸预防老年肌少症方法的建立
  • 批准号:
    15K08916
  • 财政年份:
    2015
  • 资助金额:
    $ 54.98万
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针灸治疗肌肉萎缩的临床应用基础研究
  • 批准号:
    26870555
  • 财政年份:
    2014
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    $ 54.98万
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    Grant-in-Aid for Young Scientists (B)
A Method for Evaluating Acupuncture Therapy in Pain Management
评估针灸治疗疼痛的方法
  • 批准号:
    8518241
  • 财政年份:
    2009
  • 资助金额:
    $ 54.98万
  • 项目类别:
A Method for Evaluating Acupuncture Therapy in Pain Management
评估针灸治疗疼痛的方法
  • 批准号:
    8294798
  • 财政年份:
    2009
  • 资助金额:
    $ 54.98万
  • 项目类别:
A Method for Evaluating Acupuncture Therapy in Pain Management
评估针灸治疗疼痛的方法
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    7935165
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A Method for Evaluating Acupuncture Therapy in Pain Management
评估针灸治疗疼痛的方法
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    8111166
  • 财政年份:
    2009
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A Method for Evaluating Acupuncture Therapy in Pain Management
评估针灸治疗疼痛的方法
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    7845141
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