In the 17th century, Thomas Dekker wrote “Do but consider what an excellent thing sleep is...that golden chain that ties health and our bodies together.” It is commonly accepted that little or no sleep can affect our well-being. A recent study in Nature medicine now provides scientific evidence that lack of sleep can increase pain sensitivity in mice and points towards a significant role of alertness. These two findings were quite unexpected as co-first authors Dr. Chloe Alexandre and Dr. Alban Latremoliere from Harvard Medical School explain, “Firstly, the potent pain-killer morphine lost most of its efficacy in sleep-deprived mice. Secondly, moderate but repeated sleep deprivation increased pain hypersensitivity over time, despite some opportunities for sleep each day. This reinforces the notion that sleep is indispensable, despite our desire to stay awake more.”
A stress-free mouse model lack of sleep
The first remarkable achievement of this study is the development of a stress-free sleep-deprived mouse model, which was essential to understand the effect of sleep deprivation itself. The authors monitored the electroencephalogram and electromyogram of the animals and when measurements indicated that they were falling asleep a novel object was placed in the cage providing entertainment that kept the mice awake.
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A sleepless night or a few short nights of sleep are detrimental
The pain sensitivity was measured using various noxious stimuli such as mechanical pressure, heat or capsaicin - the molecule that makes chilli peppers hot. A single sleepless night (9 or 12h) was enough to exaggerate the response to those noxious stimuli as both males and females licked and withdrew their paws from the stimuli significantly more than the fully rested control animals. Interestingly, those effects were erased by a 24h recovery sleep. Using the same paradigm mice were subjected to a 6h sleep deprivation, a time that did not affect their pain threshold, for 5 consecutive days. This chronic moderate sleep deprivation induced an increased sensitivity to noxious stimuli, like that observed for acute sleep deprivation.
Lead authors of the study, Drs Chloe Alexandre and Alban Latremoliere. Harvard Medical School.
“Our results show that even under normal conditions, without any injury or inflammation, pain sensitivity is not hard-set, but instead fully integrated into the general state of the animal, implying that your sleep history could represent a major modulator of your pain sensitivity. This is something that has not been carefully looked at before.” said Drs Alexandre and Latremoliere.
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Stimulating alertness is beneficial
Interestingly, pain-relieving drugs such as ibuprofen or morphine did not improve the sleep deprivation-induced pain hypersensitivity while substances stimulating the dopaminergic system such as caffeine and modafinil did. Their pain-relieving effects in sleep-deprived mice suggest that a decrease in general wakefulness was responsible for the increased pain sensitivity of the sleep-deprived mice.
However, the question of how alertness affects pain sensitivity is still an open one, as the authors explain, “Our results with caffeine and modafinil point towards a role of dopamine transmission in the increased pain sensitivity caused by sleep loss. Dopamine in the mesolimbic system is critical to determine how ‘noticeable’ a stimulus is, and we now want to know exactly how this modulates pain sensitivity in sleep deprived or well-rested mice.”
A new approach to pain assessment and treatment?
This work brings new understanding that adds to the complexity of the mechanisms of pain sensitivity, as the authors point out, “These data highlight the importance of getting enough sleep, and that insufficient sleep can profoundly affect pain sensitivity, even in otherwise healthy individuals.”
Moreover, their study has many potential implications for both the treatment and evaluation of pain. Indeed, pain assessment can be influenced by the general level of wakefulness of the patient or simply by their coffee intake. Additionally, pain management in patients suffering from chronic pain could also benefit from their study as the authors explain, “We find that morphine’s efficacy is strongly reduced in sleep-deprived animals, and if this is also true in patients this could lead to an increased consumption of pain medications, more side effects, and more potential for abuse of medications. Treating pain patients for their sleep problems (through better sleep hygiene or pharmacological means) could therefore be beneficial to reduce their pain, and also restore the efficacy of their pain treatments.” Therefore, this study not only highlights the importance of a regular good-quality sleep but opens-up new opportunities for patients suffering from chronic pain.
Also read: sleep is key to curing chronic pain
Alexandre C, Latremoliere A, Ferreira A, Miracca G, Yamamoto M, Scammell TE, Woolf CJ. 2017. Decreased alertness due to sleep loss increases pain sensitivity in mice. Nature Medicine doi:10.1039/nm.4329