Decreased alertness due to sleep loss increases pain sensitivity in mice

Abstract

Extended daytime and nighttime activities are major contributors to the growing sleep deficiency epidemic1,2, as is the high prevalence of sleep disorders like insomnia. The consequences of chronic insufficient sleep for health remain uncertain3. Sleep quality and duration predict presence of pain the next day in healthy subjects4,5,6,7, suggesting that sleep disturbances alone may worsen pain, and experimental sleep deprivation in humans supports this claim8,9. We demonstrate that sleep loss, but not sleep fragmentation, in healthy mice increases sensitivity to noxious stimuli (referred to as 'pain') without general sensory hyper-responsiveness. Moderate daily repeated sleep loss leads to a progressive accumulation of sleep debt and also to exaggerated pain responses, both of which are rescued after restoration of normal sleep. Caffeine and modafinil, two wake-promoting agents that have no analgesic activity in rested mice, immediately normalize pain sensitivity in sleep-deprived animals, without affecting sleep debt. The reversibility of mild sleep-loss-induced pain by wake-promoting agents reveals an unsuspected role for alertness in setting pain sensitivity. Clinically, insufficient or poor-quality sleep may worsen pain and this enhanced pain may be reduced not by analgesics, whose effectiveness is reduced, but by increasing alertness or providing better sleep.

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Figure 1: Acute sleep deprivation progressively increases sleepiness and sensitivity to pain.
Figure 2: Chronic sleep deprivation progressively increases sleepiness.
Figure 3: Chronic sleep deprivation but not chronic sleep fragmentation progressively increases pain sensitivity.
Figure 4: Caffeine and modafinil, but not ibuprofen or morphine, prevent sleep-deprivation-induced hypersensitivity to pain.

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Acknowledgements

This work was supported by NIH grants DE022912 (C.J.W. and T.E.S.), NS038253-11S1 (C.J.W.) and HL095491 (T.E.S.), the IDDRC of Boston Children's Hospital (U54 HD090255) and the Metabolic Physiology Core (P30 DK057521). We are grateful to N. Andrews, O. Peroni, F. Latremoliere, T. Mochizuki, P.-A. Libourel and R. Hersher for advice and technical assistance and O. Mazor of the HMS Research Instrumentation Core for instrument design and fabrication.

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C.A., A.L., T.E.S. and C.J.W. conceived and designed experiments, interpreted the results and wrote the manuscript. C.A., A.L., A.F. and G.M. performed sleep studies and analysis. C.A., A.L., A.F., G.M. and M.Y. performed sleep deprivation experiments. C.A., A.L. and A.F. performed behavioral experiments and analysis.

Corresponding authors

Correspondence to Thomas E Scammell or Clifford J Woolf.

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The authors declare no competing financial interests.

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Alexandre, C., Latremoliere, A., Ferreira, A. et al. Decreased alertness due to sleep loss increases pain sensitivity in mice. Nat Med 23, 768–774 (2017). https://doi.org/10.1038/nm.4329

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