Difficulty sleeping can be both a result of chronic pain and a contributor to it. Indeed, poor sleep is a known risk factor for chronic pain,¹ and there is general consensus about this relationship in both the clinical and scientific community, noted Jonathan Elliott, PhD. Dr. Elliott serves as an assistant professor of neurology in the Oregon Health Sciences University School of Medicine and a research physiologist at the VA Portland Health Care System.

A study published in January 2023 in Nature Neuroscience may shed some light on this complex and often mysterious relationship while also offering better ways to treat pain.²

Hyperactive Neurons

Researchers at Columbia University Medical Center and New York University School of Medicine used mice with spared nerve injury (SNI), a common method of studying neuropathic pain in animal models, to examine the changes to somatosensory circuits caused by pain. They cut two branches of the sciatic nerve in the thighs of the animals, leaving the sural nerve intact, thus creating a hypersensitivity typical of neuropathic pain due to peripheral nerve injury. In the control animals, the sciatic nerve was exposed for sham surgery, but not cut.

Before and after surgery, the researchers monitored brain activity in the mice. They found hyperactivity in S1 pyramidal neurons (PNs) during wakefulness and during nonrapid eye movement (NREM) sleep, but not during rapid eye movement (REM) sleep. This hyperactivity was more pronounced during NREM sleep than during periods of quiet wakefulness. The hyperactivation of S1 PNs increased during the weeks following the surgery, as the pain became chronic.

Potential for Neural Pain Treatments

The findings indicate that the PB-aNB-S1 pathway during sleep is crucial for generating and maintaining chronic pain, further suggesting that timing of treatment is crucial. The team also found that inhibiting this pathway during NREM sleep, but notably not during wakefulness, corrected the neuronal hyperactivity and alleviated the pain.

“We find that neuronal inhibition during the rest phase or NREM sleep is maximally effective in achieving sustained pain relief, even in mice with established chronic neuropathic pain,” wrote the researchers.²

If these findings apply to humans as well as mice, inhibiting this pathway during the deep sleep phase could be an important strategy for treating chronic neuropathic pain in humans.

“However, epidemiological studies have consistently demonstrated that poor sleep quality and insufficient sleep duration are significant risk factors for the development of chronic pain in humans. It is thus possible that similar mechanisms also occur in humans.”

While the researchers acknowledge that they do not know how neuronal activity in sleep encodes chronic pain memory in the neural network, nor whether sleep alterations contribute to this activation, their results do suggest that pain memory is encoded in the brain during sleep much the same way other memories are.

“Our studies in mice suggest that chronic pain may be consolidated during sleep,” Dr. Yang said. “They suggest that pharmacological treatment for pain may be dependent on when the drugs are administrated (sleep or awake). In addition, it might be of interest to consider manipulating the activity of specific circuits related to pain consolidation during sleep.”

  1. Haack M, Simpson N, Sethna N, et al. Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications. Neuropsychopharmacology. 2020;45(1):205-216. doi:10.1038/s41386-019-0439-z
  2. Zhou H, Li M, Zhao R, et al. A sleep-active basalocortical pathway crucial for generation and maintenance of chronic pain [published online ahead of print, 2023 Jan 23]. Nat Neurosci. 2023;10.1038/s41593-022-01250-y.