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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References
Van den Bulck, J. Television viewing, computer game playing, and Internet use and self-reported time to bed and time out of bed in secondary-school children. Sleep 27, 101–104 (2004).
Fossum, I.N., Nordnes, L.T., Storemark, S.S., Bjorvatn, B. & Pallesen, S. The association between use of electronic media in bed before going to sleep and insomnia symptoms, daytime sleepiness, morningness, and chronotype. Behav. Sleep Med. 12, 343–357 (2014).
Luyster, F.S., Strollo, P.J. Jr., Zee, P.C. & Walsh, J.K. Sleep: a health imperative. Sleep 35, 727–734 (2012).
Edwards, R.R., Almeida, D.M., Klick, B., Haythornthwaite, J.A. & Smith, M.T. Duration of sleep contributes to next-day pain report in the general population. Pain 137, 202–207 (2008).
Campbell, C.M. et al. Self-reported sleep duration associated with distraction analgesia, hyperemia, and secondary hyperalgesia in the heat–capsaicin nociceptive model. Eur. J. Pain 15, 561–567 (2011).
Haack, M. et al. Pain sensitivity and modulation in primary insomnia. Eur. J. Pain 16, 522–533 (2012).
Smith, M.T., Edwards, R.R., Stonerock, G.L. & McCann, U.D. Individual variation in rapid eye movement sleep is associated with pain perception in healthy women: preliminary data. Sleep 28, 809–812 (2005).
Lautenbacher, S., Kundermann, B. & Krieg, J.C. Sleep deprivation and pain perception. Sleep Med. Rev. 10, 357–369 (2006).
Roehrs, T., Hyde, M., Blaisdell, B., Greenwald, M. & Roth, T. Sleep loss and REM sleep loss are hyperalgesic. Sleep 29, 145–151 (2006).
Mansfield, K.E., Sim, J., Jordan, J.L. & Jordan, K.P. A systematic review and meta-analysis of the prevalence of chronic widespread pain in the general population. Pain 157, 55–64 (2016).
Finan, P.H., Goodin, B.R. & Smith, M.T. The association of sleep and pain: an update and a path forward. J. Pain 14, 1539–1552 (2013).
Smith, M.T. et al. Sleep onset insomnia symptoms during hospitalization for major burn injury predict chronic pain. Pain 138, 497–506 (2008).
Davies, K.A. et al. Restorative sleep predicts the resolution of chronic widespread pain: results from the EPIFUND study. Rheumatology (Oxford) 47, 1809–1813 (2008).
Kim, H. et al. Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain 109, 488–496 (2004).
Kuna, S.T. et al. Heritability of performance deficit accumulation during acute sleep deprivation in twins. Sleep 35, 1223–1233 (2012).
Meerlo, P., Pragt, B.J. & Daan, S. Social stress induces high intensity sleep in rats. Neurosci. Lett. 225, 41–44 (1997).
Rhudy, J.L. & Meagher, M.W. Fear and anxiety: divergent effects on human pain thresholds. Pain 84, 65–75 (2000).
Kaprio, J. & Koskenvuo, M. Genetic and environmental factors in complex diseases: the older Finnish Twin Cohort. Twin Res. 5, 358–365 (2002).
Nielsen, C.S. et al. Individual differences in pain sensitivity: genetic and environmental contributions. Pain 136, 21–29 (2008).
Leemburg, S. et al. Sleep homeostasis in the rat is preserved during chronic sleep restriction. Proc. Natl. Acad. Sci. USA 107, 15939–15944 (2010).
Clasadonte, J., McIver, S.R., Schmitt, L.I., Halassa, M.M. & Haydon, P.G. Chronic sleep restriction disrupts sleep homeostasis and behavioral sensitivity to alcohol by reducing the extracellular accumulation of adenosine. J. Neurosci. 34, 1879–1891 (2014).
Hakki Onen, S., Alloui, A., Jourdan, D., Eschalier, A. & Dubray, C. Effects of rapid eye movement (REM) sleep deprivation on pain sensitivity in the rat. Brain Res. 900, 261–267 (2001).
Tomim, D.H. et al. The pronociceptive effect of paradoxical sleep deprivation in rats: evidence for a role of descending pain modulation mechanisms. Mol. Neurobiol. 53, 1706–1717 (2016).
Wang, P.K. et al. Short-term sleep disturbance–induced stress does not affect basal pain perception, but does delay postsurgical pain recovery. J. Pain 16, 1186–1199 (2015).
Boada, M.D. & Woodbury, C.J. Physiological properties of mouse skin sensory neurons recorded intracellularly in vivo: temperature effects on somal membrane properties. J. Neurophysiol. 98, 668–680 (2007).
Boada, M.D. & Woodbury, C.J. Myelinated skin sensory neurons project extensively throughout adult mouse substantia gelatinosa. J. Neurosci. 28, 2006–2014 (2008).
Borbély, A.A. & Achermann, P. Sleep homeostasis and models of sleep regulation. J. Biol. Rhythms 14, 557–568 (1999).
Mignot, E. Why we sleep: the temporal organization of recovery. PLoS Biol. 6, e106 (2008).
Haack, M., Lee, E., Cohen, D.A. & Mullington, J.M. Activation of the prostaglandin system in response to sleep loss in healthy humans: potential mediator of increased spontaneous pain. Pain 145, 136–141 (2009).
Fredholm, B.B., Bättig, K., Holmén, J., Nehlig, A. & Zvartau, E.E. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol. Rev. 51, 83–133 (1999).
Qu, W.M., Huang, Z.L., Xu, X.H., Matsumoto, N. & Urade, Y. Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil. J. Neurosci. 28, 8462–8469 (2008).
Huang, Z.L. et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat. Neurosci. 8, 858–859 (2005).
Petrovsky, N. et al. Sleep deprivation disrupts prepulse inhibition and induces psychosis-like symptoms in healthy humans. J. Neurosci. 34, 9134–9140 (2014).
Schuh-Hofer, S. et al. One night of total sleep deprivation promotes a state of generalized hyperalgesia: a surrogate pain model to study the relationship of insomnia and pain. Pain 154, 1613–1621 (2013).
Ødegård, S.S. et al. The effect of sleep restriction on laser evoked potentials, thermal sensory and pain thresholds and suprathreshold pain in healthy subjects. Clin. Neurophysiol. 126, 1979–1987 (2015).
Tiede, W. et al. Sleep restriction attenuates amplitudes and attentional modulation of pain-related evoked potentials, but augments pain ratings in healthy volunteers. Pain 148, 36–42 (2010).
Ferraro, L. et al. The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism. Eur. J. Pharmacol. 306, 33–39 (1996).
Solinas, M. et al. Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. J. Neurosci. 22, 6321–6324 (2002).
Volkow, N.D. et al. Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. J. Am. Med. Assoc. 301, 1148–1154 (2009).
Volkow, N.D. et al. Evidence that sleep deprivation downregulates dopamine D2R in ventral striatum in the human brain. J. Neurosci. 32, 6711–6717 (2012).
Volkow, N.D. et al. Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain. Transl. Psychiatry 5, e549 (2015).
Bonaventura, J. et al. Allosteric interactions between agonists and antagonists within the adenosine A2A receptor–dopamine D2 receptor heterotetramer. Proc. Natl. Acad. Sci. USA 112, E3609–E3618 (2015).
Taylor, A.M., Becker, S., Schweinhardt, P. & Cahill, C. Mesolimbic dopamine signaling in acute and chronic pain: implications for motivation, analgesia, and addiction. Pain 157, 1194–1198 (2016).
Treister, R. et al. Associations between polymorphisms in dopamine neurotransmitter pathway genes and pain response in healthy humans. Pain 147, 187–193 (2009).
Wood, P.B. et al. Fibromyalgia patients show an abnormal dopamine response to pain. Eur. J. Neurosci. 25, 3576–3582 (2007).
Edwards, R.R. et al. Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations. Pain 157, 1851–1871 (2016).
Skinner, G.O., Damasceno, F., Gomes, A. & de Almeida, O.M. Increased pain perception and attenuated opioid antinociception in paradoxical sleep-deprived rats are associated with reduced tyrosine hydroxylase staining in the periaqueductal gray matter and are reversed by l-DOPA. Pharmacol. Biochem. Behav. 99, 94–99 (2011).
Steinmiller, C.L. et al. Differential effect of codeine on thermal nociceptive sensitivity in sleepy versus nonsleepy healthy subjects. Exp. Clin. Psychopharmacol. 18, 277–283 (2010).
Faraut, B. et al. Napping reverses increased pain sensitivity due to sleep restriction. PLoS One 10, e0117425 (2015).
Roehrs, T.A., Harris, E., Randall, S. & Roth, T. Pain sensitivity and recovery from mild chronic sleep loss. Sleep 35, 1667–1672 (2012).
Sorge, R.E. et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat. Methods 11, 629–632 (2014).
Latremoliere, A. et al. Reduction of neuropathic and inflammatory pain through inhibition of the tetrahydrobiopterin pathway. Neuron 86, 1393–1406 (2015).
Choi, Y., Yoon, Y.W., Na, H.S., Kim, S.H. & Chung, J.M. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain 59, 369–376 (1994).
Smith, S.B., Crager, S.E. & Mogil, J.S. Paclitaxel-induced neuropathic hypersensitivity in mice: responses in 10 inbred mouse strains. Life Sci. 74, 2593–2604 (2004).
Vicuña, L. et al. The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell–derived leukocyte elastase. Nat. Med. 21, 518–523 (2015).
Le Bars, D., Gozariu, M. & Cadden, S.W. Animal models of nociception. Pharmacol. Rev. 53, 597–652 (2001).
Mogil, J.S. et al. Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception. Pain 80, 67–82 (1999).
Mogil, J.S. Animal models of pain: progress and challenges. Nat. Rev. Neurosci. 10, 283–294 (2009).
Sandkühler, J. Models and mechanisms of hyperalgesia and allodynia. Physiol. Rev. 89, 707–758 (2009).
Moqrich, A. et al. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307, 1468–1472 (2005).
Caterina, M.J. et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306–313 (2000).
Davis, M. Neurochemical modulation of sensory-motor reactivity: acoustic and tactile startle reflexes. Neurosci. Biobehav. Rev. 4, 241–263 (1980).
Geyer, M.A., McIlwain, K.L. & Paylor, R. Mouse genetic models for prepulse inhibition: an early review. Mol. Psychiatry 7, 1039–1053 (2002).
Alexandre, C. et al. Sleep-stabilizing effects of E-6199, compared to zopiclone, zolpidem and THIP in mice. Sleep 31, 259–270 (2008).
Hennessy, M.B. & Foy, T. Nonedible material elicits chewing and reduces the plasma corticosterone response during novelty exposure in mice. Behav. Neurosci. 101, 237–245 (1987).
Libourel, P.A., Corneyllie, A., Luppi, P.H., Chouvet, G. & Gervasoni, D. Unsupervised online classifier in sleep scoring for sleep deprivation studies. Sleep 38, 815–828 (2015).
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.
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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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DOI: https://doi.org/10.1038/nm.4329
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