Pain physiologist Alban Latremoliere, PhD, of Boston Children's and sleep physiologist Chloe Alexandre, PhD, of BIDMC precisely measured the effects of chronic sleep loss on sleepiness and sensitivity to painful and non-painful stimuli.
They tested standard pain medications, like ibuprofen and morphine, as well as wakefulness-promoting agents like caffeine and modafinil. Their findings reveal an unexpected role for alertness in setting pain sensitivity.
The team measured normal sleep cycles with tiny headsets that took electroencephalography (EEG) and electromyography (EMG) readings. "For each mouse, we have exact baseline data on how much they sleep and what their sensory sensitivity is," says Latremoliere, who works in the lab of Clifford Woolf, PhD, in the F.M. Kirby Neurobiology Center at Boston Children's.
To keep the mice awake, researchers provided custom-made toys as interest flagged while being careful not to overstimulate them. "Mice love nesting, so when they started to get sleepy (as seen by their EEG/EMG pattern) we would give them nesting materials like a wipe or cotton ball," says Latremoliere.
"Rodents like chewing, so we introduced a lot of activities based around chewing, for example, having to chew through something to get to a cotton ball." In this way they kept
groups of six to 12 mice awake for as long as 12 hours in one session, or six hours for five consecutive days, monitoring sleepiness and stress hormones (to make sure they weren't stressed) and testing for pain.
Pain sensitivity was measured in a blinded fashion by exposing mice to controlled amounts of heat, cold, pressure or capsaicin and then measuring how long it took the animal to move away or lick away the discomfort caused by capsaicin.
Researchers also tested responses to non-painful stimuli, such as jumping when startled by a sudden loud sound.
"We found that five consecutive days of moderate sleep deprivation can significantly exacerbate pain sensitivity over time in healthy mice," says Alexandre.
"The response was specific to pain, and was not due to a state of general hyperexcitability to any stimuli.
Surprisingly, common analgesics like ibuprofen did not block sleep-loss-induced pain hypersensitivity. Even morphine lost most of its efficacy in sleep-deprived mice.
These observations suggest that patients using these drugs for pain relief might have to increase their dose to compensate for lost efficacy due to sleep loss, thereby increasing their risk for side effects. In contrast, caffeine
and modafinil, drugs used to promote wakefulness, successfully blocked the pain hypersensitivity caused by both acute and chronic sleep loss.
Interestingly, in non-sleep-deprived mice, these compounds had no analgesic properties. Researchers conclude that rather than just taking painkillers, patients with chronic pain might benefit from better sleep habits or sleep-promoting medications at night.
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