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There’s an Important Reason Disturbed Sleep Makes Everything Hurt More

There’s an Important Reason Disturbed Sleep Makes Everything Hurt More

Posted on November 7, 2023 Updated on November 6, 2023

Ever feel like everything hurts after not getting enough sleep? A new study reveals a neurotransmitter involved in the pain that sleep deprivation causes, indicating a potential new target for treatment.

In sleep-deprived mouse models, the neurotransmitter N-arachidonoyl dopamine (NADA), an endocannabinoid, was reduced in one brain region linked to sensory processing and arousal.

Administration of NADA to this region alleviated the previously heightened pain response.

Unsurprisingly, sleep problems are common in people who already experience chronic pain. But in turn, having trouble sleeping exacerbates the nervous system’s response to potentially painful stimuli and makes pain feel worse.

Of course, we’d expect sleep loss to make many things worse. But the pathways that cause people to experience headaches and body pain after lack of sleep haven’t been well defined, making it harder to treat.

“We provide a mechanism as to how sleep disruption leads to exaggerated pain, suggesting that harnessing the endocannabinoid system might break the vicious cycle between pain and sleep loss,” says co-senior author Shiqian Shen, a anesthesiologist and pain physician from Harvard Medical School.

Shen and colleagues from the US, China, and South Korea conducted tests on mice and found chronic sleep disruption made them more sensitive to pain, and this was caused by signaling from a part of the brain called the thalamic reticular nucleus (TRN).

The TRN has roles in regulating alertness, and it’s thought to act like a gatekeeper that controls the flow of sensory information to the cortex, the outer layer of neurons in our brains.

Past studies in mice have implicated the TRN in pain sensitivity, so the team wanted to investigate if this could apply to the kind of pain caused by not enough shut-eye.

Mice that underwent five consecutive days of sleep deprivation showed higher sensitivity in tests designed to measure response to pain. Brain signal measurements showed exaggerated activation of specific neurons in the TRN that project to an area of the thalamus that relays sensations like pain, touch, and temperature to the cortex.

Looking at brain metabolites, the researchers discovered that the endocannabinoid NADA levels were lower in the TRN of mice that had not slept enough compared to control mice. This drop was only seen in the TRN.

When Shen and team administered NADA to the TRN of sleep-deprived mice, the increased activation of those neurons signaling to the thalamus region was reversed, and the mice no longer showed signs of heightened pain sensitivity.

“Our results suggest that NADA is physiologically important and that chronic sleep disruption leads to decreased NADA levels which underlies hyperalgesia [heightened sensitivity to pain],” the team writes.

Endocannabinoids are lipid-based signaling molecules produced naturally in our bodies. They bind to cannabinoid receptors in the endocannabinoid system, a complex cell signaling system involved in regulating a wide range of bodily functions.

The researchers also found that cannabinoid receptor 1 activity, which is involved in regulating pain perception, decreased in the TRN of sleep-deprived mice. Then, they demonstrated that blocking cannabinoid receptor 1 can counteract NADA’s beneficial effects.

This suggests that both the receptor and NADA contribute to increased pain sensitivity in mice when they’re sleep deprived.

Endocannabinoids have been implicated in many neurological disorders, including multiple sclerosis, Parkinson’s disease, Alzheimer’s, and epilepsy.

It looks like they play a major part in regulating chronic pain associated with sleep loss, too. The team hopes their findings about NADA’s role will lead to more effective therapies.

“These findings provide mechanistic insights into the neuronal circuitry underlying chronic sleep disruption-induced hyperalgesia,” the researchers conclude, “and implicate endocannabinoids as potential mechanistic targets for future study.”

The research has been published in Nature Communications.

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