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

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $549,780

## Abstract

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 c...

## Key facts

- **NIH application ID:** 10213385
- **Project number:** 1R01AT011439-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Maiken Nedergaard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $549,780
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213385

## Citation

> US National Institutes of Health, RePORTER application 10213385, The glymphatic system at the crossroad of integrative health approaches inchronic pain (1R01AT011439-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10213385. Licensed CC0.

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