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.

摘要：淋巴系统是一个血管周围空间网络，具有废物清除系统的功能。