The Glymphatic System and Pain

Abstract

The glymphatic system is network of perivascular spaces through which cerebrospinal fluid and interstitial fluid can move through the brain, clearing metabolic waste, such as amyloid beta, lactate and more, from the parenchyma. This cleaning system is regulated by sleep and norepinephrine, with increased levels of norepinephrine during wakefulness inhibiting fluid movement. Norepinephrine is also essential for transition from acute to chronic pain, and sufferers of chronic neuropathic pain frequently present with sleep disruption. These connections among glymphatic clearance, sleep, and pain are very intriguing, and might lead to nonpharmaceutical interventions for pain treatment. This short perspective provides a rationale for the hypothesis that mind-body interventions-such as acupuncture-can reduce norepinephrine and increase glymphatic function, ultimately relieving chronic neuropathic pain.

Evaluation of the Glymphatic System With Diffusion Tensor Imaging-Along the Perivascular Space in Cancer Pain

“…This results in a decrease in diffusivity, which reflects the drainage directions of the myelinated fiber tracts and perivascular space ( Li et al, 2020 ). (2) The release of neurotransmitters, such as norepinephrine, increases under chronic pain stimulation, which may cause arteries in the brain to contract and decrease pulsation, affecting the function of the glymphatic system ( Xie et al, 2013 ; IsHak et al, 2018 ; Goldman et al, 2020 ). Norepinephrine promotes the activation of microglia, which interact with other brain cells, such as neurons and astrocytes, via ‘crosstalk,’ causing changes in the activity and metabolism of cells, further affecting the function of the glymphatic system ( Malcangio, 2019 ).…”

“…In the future, the ALPS index, combined with biological indicators, such as gene polymorphisms, may allow more objective and individualized CP assessments. Furthermore, the association between the glymphatic system and pain stimulation may help in the development of non-pharmaceutical interventions for pain, where pain may be alleviated via the regulation of glymphatic function ( Goldman et al, 2020 ).…”

“…Increasingly, studies have shown that impairment of the drainage and clearance function of the glymphatic system is closely related to several mental and neurodegenerative diseases, such as depression, Alzheimer’s disease (AD), and Parkinson’s disease (PD) ( Lei et al, 2017 ; Rasmussen et al, 2018 ; Hablitz and Nedergaard, 2021 ; Yan et al, 2021 ). Furthermore, several studies have reported that peripheral pain stimulation induces spatial structural alterations and decreased drainage function of the ECS in the deep brain ( Goldman et al, 2020 ; Li et al, 2020 ). More importantly, chronic pain is a vital risk factor for depression and cognitive impairment ( Jenny Wei et al, 2021 ).…”

Glymphatic System Dysfunction: A Novel Mediator of Sleep Disorders and Headaches

“…They may directly influence each other via the GS; for example, sleep can decline NE levels from the locus coeruleus, thereby increasing the size of the interstitial space, lowering the resistance to convective fluid movement, and promoting CSF influx and interstitial solute efflux, thus it can improve the closure of PVS by CSD to alleviate the symptoms of migraine ( 11 , 24 ); pain may directly block GS function by altering neuronal function, which in turn, causes sleep disturbances. Alternatively, there may be an indirect connection, whereby sleep disruption causes the accumulation of a large amount of metabolic waste, which triggers neuroinflammation and impairment of the GS, inducing intense headache symptoms ( 6 , 50 , 53 ). Thus, improving sleep quality can improve GS function by enlarging PVS, increasing CSF-ISF exchange, and promoting metabolic waste removal to relieve headaches.…”

“…The glymphatic system (GS) is a newly discovered central nervous system (CNS) waste cleaning system that may offer a possible explanation for the relationship between sleep and headache ( 6 ). Its function is similar to the peripheral lymphatic system and relies on astrocytes; thus, the system is termed a “glia lymphatic” or “glymphatic” system, which represents a waste clearance and fluid pathway in and out of the brain ( 7 , 8 ).…”