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:10453615
- 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
- 来源:
- 关键词:Absence of pain sensationAcupuncture TherapyAcute PainAgeAgingAlcohol consumptionAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAnalgesicsAnteriorArousalBiological MarkersBrainCardiovascular DiseasesCardiovascular systemChronicChronic stressComplementary HealthDataDiabetes MellitusDrainage procedureEicosapentaenoic AcidExerciseGoalsHeavy DrinkingHyperalgesiaHypersensitivityHypertensionImmune systemInflammationIntegrative MedicineInterventionLightLymphatic SystemLymphatic clearanceMedicalMelatoninMetabolicMetabolic syndromeMicrodialysisMind-Body InterventionModelingModernizationMusNeural PathwaysNorepinephrineOmega-3 Fatty AcidsOperating SystemPainPathologyPathway interactionsPeripheralPharmacologyPhenotypeProcessResearch PersonnelRestSeveritiesSleepSleep DeprivationSleep disturbancesStressSystemTechniquesTemperatureTestingTherapeuticTimeTraumatic Brain InjuryTreatment EfficacyWakefulnessWorkallodyniabasebody-mindchronic neuropathic painchronic painchronic pain managementchronic pain patientcingulate cortexcircadiancytokineexperienceglymphatic clearanceglymphatic flowglymphatic functionglymphatic systemimprovedimprovement on sleepinterestmouse modelnerve injuryneuronal excitabilitypain modelpain perceptionpain reductionpain reliefpain sensitivitypainful neuropathypatient populationpoor sleeppre-clinicalresponsesleep qualitysolutetargeted treatmenttreatment effectwasting
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:类淋巴系统是血管周围空间的网络,具有废物清除系统的功能,
类似于外周淋巴系统。类淋巴功能降低已成为一个标志性观察结果
衰老以及阿尔茨海默病、糖尿病、高血压、脑外伤、过量饮酒的模型
摄入量和慢性不可预测的压力。初步数据显示,急性和慢性疼痛以及一晚的疼痛
光所有抑制类淋巴功能。该应用程序将使用小鼠稀疏神经损伤(SNI)模型来
了解大脑如何应对慢性神经性疼痛。睡眠问题在慢性疼痛中很常见
患者,长期睡眠限制会增加小鼠的疼痛敏感性。去甲肾上腺素(NE),会破坏
睡眠中并在压力条件下释放,抑制类淋巴功能。我们假设增加 NE
SNI 水平会降低类淋巴功能,引发细胞因子积累、神经元兴奋性、睡眠中断
和前馈循环中的疼痛敏化(目标 1)。传统镇痛药已被证明可以缓解疼痛
慢性疼痛模型。我们的初步数据表明,相同的药物可以恢复 SNI 小鼠的类淋巴功能
对对照小鼠的类淋巴功能没有影响。我们假设通过以下方式减轻疼痛的严重程度
镇痛通过降低 NE 水平来改善类淋巴功能,从而减少细胞因子的积累和
兴奋性并改善睡眠质量(目标 2.1)。然而,现代药理学的功效对患者来说是可变的
人群,表明虽然神经通路的调节部分有效,但病理仍然存在。我们
假设神经性疼痛会引起中枢神经系统适应不良反应,涉及类淋巴液流量减少,
炎症和废物堆积。因为自然干预和身心干预都针对多个方面
类淋巴系统紊乱(睡眠、炎症、心血管疾病),我们假设天然补充剂
(褪黑激素和二十碳五烯酸(一种 ω-3 脂肪酸))和身心干预(自愿锻炼、
改善睡眠和针灸)将改善慢性疼痛中的类淋巴系统紊乱(目标 2.2 和 2.3)。这
治疗时机至关重要,因为昼夜节律系统融入了身体的每个过程,包括
类淋巴系统、免疫系统和慢性疼痛。我们建议通过靶向治疗来强化
类淋巴功能和清除的节律将优化治疗效果,可以量化为
SNI 中细胞因子积累和痛觉过敏的进一步减少(目标 3)。我们会定时睡觉
通过提高体温、自愿锻炼、褪黑激素和针灸来改善内源性
脑脊液分布节律——休息时类淋巴液清除率高,清醒时低。目标 3 是独一无二的
因为它测试了身心疗法在改善类淋巴功能和减轻疼痛方面是否有效
敏感性,可以根据一天中给药的时间而变化。总体而言,该应用程序旨在
定义类淋巴活性是否可以作为补充治疗方法的目标,也可以作为
确定治疗效果的生物标志物。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Maiken Nedergaard其他文献
Maiken Nedergaard的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Maiken Nedergaard', 18)}}的其他基金
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:
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:
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:
10626911 - 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:
相似海外基金
Acupuncture therapy for fatigue of hemodialysis patients - Double-blind RCT study by the autonomic nervous system.
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:
17K09291 - 财政年份:2017
- 资助金额:
$ 54.98万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
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:
9999445 - 财政年份: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 - 项目类别:
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 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Basic research for clinical application of acupuncture therapy for muscle atrophy
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
- 资助金额:
$ 54.98万 - 项目类别:
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
- 批准号:
7935165 - 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:
8111166 - 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:
7845141 - 财政年份:2009
- 资助金额:
$ 54.98万 - 项目类别: