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
• 负责人: Maiken Nedergaard
• 金额: $ 54.98万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10453615
• 关键词: Absence of pain sensation; Acupuncture Therapy; Acute Pain; Age; Aging; Alcohol consumption; Alzheimer' s Disease; Alzheimer' s disease model; Analgesics; Anterior; Arousal; Biological Markers; Brain; Cardiovascular Diseases; Cardiovascular system; Chronic; Chronic stress; Complementary Health; Data; Diabetes Mellitus; Drainage procedure; Eicosapentaenoic Acid; Exercise; Goals; Heavy Drinking; Hyperalgesia; Hypersensitivity; Hypertension; Immune system; Inflammation; Integrative Medicine; Intervention; Light; Lymphatic System; Lymphatic clearance; Medical; Melatonin; Metabolic; Metabolic syndrome; Microdialysis; Mind-Body Intervention; Modeling; Modernization; Mus; Neural Pathways; Norepinephrine; Omega-3 Fatty Acids; Operating System; Pain; Pathology; Pathway interactions; Peripheral; Pharmacology; Phenotype; Process; Research Personnel; Rest; Severities; Sleep; Sleep Deprivation; Sleep disturbances; Stress; System; Techniques; Temperature; Testing; Therapeutic; Time; Traumatic Brain Injury; Treatment Efficacy; Wakefulness; Work; allodynia; base; body-mind; chronic neuropathic pain; chronic pain; chronic pain management; chronic pain patient; cingulate cortex; circadian; cytokine; experience; glymphatic clearance; glymphatic flow; glymphatic function; glymphatic system; improved; improvement on sleep; interest; mouse model; nerve injury; neuronal excitability; pain model; pain perception; pain reduction; pain relief; pain sensitivity; painful neuropathy; patient population; poor sleep; pre-clinical; response; sleep quality; solute; targeted treatment; treatment effect; wasting

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.

翻译后摘要：胶质淋巴系统是一个网络的血管周围空间，作为废物清除系统的功能， 类似于外周淋巴系统。胶质淋巴功能降低一直是一个标志性的观察， 衰老以及阿尔茨海默病、糖尿病、高血压、创伤性脑损伤、过量酒精 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，以及一个晚上的 光都抑制胶质淋巴功能。本申请将使用鼠稀疏神经损伤（SNI）模型， 了解大脑对慢性神经性疼痛的反应。睡眠抱怨在慢性疼痛中普遍存在 慢性睡眠限制会增加小鼠的疼痛敏感性。去甲肾上腺素（NE）， 睡眠和释放在紧张的条件下，抑制胶质淋巴功能。我们假设NE增加 SNI水平降低胶质淋巴功能，触发细胞因子积累、神经元兴奋性、睡眠中断 和前馈回路中的疼痛敏化（Aim 1）。传统的止痛药已被证明可以缓解疼痛， 慢性疼痛的模型我们的初步数据表明，相同的药物恢复胶质淋巴功能，在SNI小鼠 对对照小鼠的胶质淋巴功能没有影响。我们假设通过以下方法减轻疼痛的严重程度 镇痛通过降低NE水平来改善胶质淋巴功能，从而减少细胞因子的积累， 提高睡眠质量（目标2.1）。然而，现代药理学的疗效在患者中是可变的。 人群，表明虽然神经通路的调节是部分有效的，病理仍然存在。我们 假设神经性疼痛会诱导中枢神经系统适应不良反应，包括胶质淋巴流减少， 炎症和废物积累。因为自然和身心干预都针对多个方面 胶质淋巴破坏（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（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胶质淋巴破坏（目的2.2和2.3）。的 治疗的时机是至关重要的，因为昼夜节律系统被整合到身体的每个过程中，包括 胶质淋巴系统、免疫系统和慢性疼痛。我们认为，靶向治疗，以加强 胶质淋巴功能和清除的节律将优化治疗效果，其可以量化为 SNI中细胞因子积累和痛觉过敏的额外减少（目的3）。我们会定时睡觉 通过增加温度，自愿运动，褪黑激素和针灸改善内源性 CSF分布的节律-休息时胶质淋巴清除率高，清醒时低。Aim 3独一无二 因为它测试了身心疗法在改善胶质淋巴功能和减轻疼痛方面的功效， 敏感性，可以根据一天中何时施用它们而改变。总的来说，本申请旨在 定义胶质淋巴活性是否可以作为补充治疗方法的靶点， 确定治疗效果的生物标志物。