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date: 17 January 2020

Effect of Sleep Loss on Pain

Abstract and Keywords

With the advent of modern lifestyles, there has been a significant extension of daily activities, mostly at the cost of sleep. Lack of sleep affects many biological systems, including various cognitive functions, the immune system, metabolism, and pain. Both sleep and pain are complex neurological processes that encompass many dynamic components. As a result, defining the precise interactions between these two systems represents a challenge, especially for chronic paradigms. This chapter describes how sleep is measured and how it can be experimentally altered in humans and animal models, and, in turn, how sleep disturbances, either acute or chronic, can affect different aspects of pain. Possible mechanisms involved are discussed, including an increase in inflammatory processes, a loss of nociceptive inhibitory pathways, and a defect in the cognitive processing of noxious inputs.

Keywords: sleep, non-REM sleep, sleep deprivation, chronic sleep restriction, pain, nociception, inhibitory descending controls, immune system, nucleus accumbens

Introduction

When individuals do not get sufficient sleep or have their sleep curtailed or restricted, they fail to maintain normal levels of alertness, which translates into attentional lapses and globally poor cognitive performances (Goel, Rao, Durmer, & Dinges, 2009; McHill, Hull, Wang, Czeisler, & Klerman, 2018; Van Dongen, Maislin, Mullington, & Dinges, 2003). However, insufficient sleep also negatively impacts metabolism (Spiegel, Leproult, & Van Cauter, 1999; Tasali, Leproult, Ehrmann, & Van Cauter, 2008), immune and cardiovascular functions (Faraut, Boudjeltia, Vanhamme, & Kerkhofs, 2012; Irwin, Olmstead, & Carroll, 2016; Kohansieh & Makaryus, 2015; Tobaldini, Pecis, & Montano, 2014), emotional regulation (Simon et al., 2015; Walker, 2009), and pain (Banks, 2007; Foundation, 2015; M. Smith & Haythornthwaite, 2004). With the advent of novel portable technologies, modern lifestyles have further pushed back bedtime, to a point where the current amount of sleep for an average adult (or even a child) is below standard recommendations (Badr et al., 2015; Foundation, 2005; Gradisar et al., 2013). In addition, sleep quality also deteriorated in some cases because of medical comorbidities (such as sleep apnea, mood disorders, and chronic pain), and recent studies showed that the deleterious impact of sleep disturbances is particularly significant under chronic conditions and can accumulate over time (Spiegel et al., 1999; Van Cauter, Spiegel, Tasali, & Leproult, 2008; Van Dongen et al., 2003). Furthermore, one or two nights of sleep recovery (as in a weekend) are not sufficient to fully restore performance (Banks, Van Dongen, Maislin, & Dinges, 2010).

The reciprocal relationship between sleep and pain has been extensively studied and is generally acknowledged both at the clinical and preclinical levels. A widely accepted consensus is that (1) pain stimuli disrupt sleep, (2) chronic pain conditions are commonly associated with sleep disorders, and (3) sleep loss increases pain sensitivity. However, while more than 50% of chronic pain patients indeed complain about poor sleep quality (Ohayon, 2005; M. Smith & Haythornthwaite, 2004), the remaining patients living with chronic pain do not, implying that not every type of pain disrupts sleep. Similarly, several sleep disorders are associated with increased pain complaints, such as primary insomnia (Haack et al., 2012), narcolepsy (Dauvilliers et al., 2011; Jennum, Ibsen, Knudsen, & Kjellberg, 2013), or restless leg syndrome (Hening et al., 2004), but not in all patients (Andersen, Araujo, Frange, & Tufik, 2018). Because both sleep and pain are two vital and tremendously complex physiological processes involving dynamic interactions between multiple brain nuclei (many of which have not been identified yet), it is perhaps not so surprising that their interaction is also extremely intricate and most certainly multifaceted.

In this chapter we will describe which types of sleep disturbance influence the experience of pain and how sleep can modulate nociception and pain perception through pain pathways at several levels of the nervous system. We will start by defining sleep and wake behaviors and how they can be measured in humans and rodents. Then, we will describe how sleep can be experimentally manipulated in these species and the consequences of sleep disturbance protocols on pain sensitivity, pain tolerance, and the risk of developing chronic pain. Finally, we will explore how sleep can modulate the experience of pain at different nodes of the nervous system by focusing on three main levels: the immune system, the descending inhibitory and excitatory control systems, and the reward (mesolimbic) system, which plays a critical role in setting up pain sensitivity based on alertness levels.

Defining and Measuring Sleep

All animals alternate periodically between active and quiescent states throughout the 24-hour cycle, and these define wakefulness and sleep in mammals and birds.

Definitions

All animals alternate periodically between active and quiescent states throughout the 24-hour cycle, defined as wakefulness and sleep in mammals and birds. Wakefulness is optimized to allow interactions with the environment; it is a high-arousal state characterized by consciousness, voluntary locomotor activity, and high responsiveness to sensory stimuli. Wakefulness encompasses numerous behaviors that require animals to be alert and aware of their surroundings, such as locating food, eating, drinking, exploring, evading from predators, mating, caring for offspring, or any intellectual activities such as reading a book.

In contrast, sleep is a natural, recurrent state of behavioral inactivity defined by reduced consciousness and muscle activity, a stereotypical body posture (usually at a dedicated sleep location), and reduced sensory responsiveness (Piéron, 1913; I. Tobler, 1995). Despite an increased arousal threshold, sleep is quickly reversible, which distinguishes it from other quiescent states such as torpor and hibernation, coma, or anesthesia. The latency to wake up is negatively correlated with the intensity and salience of the sensory input. For example, activation of nociceptive fibers causes a transition from sleep to wakefulness within a few hundred milliseconds in mice (Browne et al., 2017) and a few seconds in humans (Bastuji, Perchet, Legrain, Montes, & Garcia-Larrea, 2008). Awakenings can also be triggered by other sensory modalities like sound, touch, and to a lesser extent smell or light sources, depending on the most sensitive senses of the species and the salience of the stimulus.

The daily distribution and amount of sleep and wakefulness are determined by two principal and interacting systems: an endogenous circadian component that synchronizes sleep and awake periods to the environment using cues such as light, temperature, food availability, or social activities, and a homeostatic component that regulates the need and intensity of sleep according to the sleep-wake history, that is, the time previously spent asleep or awake (Borbely, 1982). Diurnal animals such as humans, apes, and dogs are mostly active during the day (light photoperiod) and sleep at night (dark photoperiod), while nocturnal animals such as rats and mice sleep the most during the light photoperiod (S. S. Campbell & Tobler, 1984). In terms of sleep patterns, humans and apes exhibit a monophasic sleep consisting of a single “consolidated” sleep block per 24-hour cycle. They are among the only species to do so, as the vast majority of mammals have a so-called polyphasic sleep, where they produce multiple sleep episodes per day. During the active period, long stretches of wakefulness are intermingled with frequent sleep episodes, while during the rest period sleep is periodically interrupted by episodes of sustained wakefulness (I. Tobler, 1995).

One of the most fundamental properties of sleep is that it is homeostatically regulated, which means the drive for sleep increases during prolonged wakefulness and dissipates during subsequent sleep (Borbely, 1982). Therefore, loss or excess of sleep triggers compensatory changes to maintain a constant sleep balance/level (Borbely, 1982). In the case of insufficient sleep, the homeostatic sleep “rebound” consists of an increase in both sleep duration and sleep intensity, which can be observed at the behavioral level by a higher arousal threshold (Borbely & Achermann, 1999).

Recording Sleep

In 1929, the German psychiatrist Hans Berger demonstrated for the first time that wakefulness and sleep exhibit distinct patterns of brain electrical activity that can be recorded at the cortical level (Berger, 1929). He analyzed the amplitude (voltage fluctuations) and the frequency of these cortical oscillations and named the overall signals “electroencephalogram” (EEG; Berger, 1929). The EEG reflects the electrical field activity generated by large groups of cortical neurons and displays large-scale oscillations which allow us to categorize them by their frequency, amplitude, and phase. This revolutionary finding started the path for modern sleep research. By separating out and classifying brain waveforms, it became possible to identify different behavioral states and link certain types of EEG activities to sensory processing and various cognitive functions. In 1953, Aserinsky and Kleitman observed for the first time that sleep is not a unitary process but comprises two major and distinct sleep states that alternate periodically throughout sleep cycles: rapid eye movement (REM) sleep and non–rapid eye movement (NREM) sleep (Aserinsky & Kleitman, 1953). These two sleep states have been observed in all terrestrial mammals and birds studies so far (S. S. Campbell & Tobler, 1984; I. Tobler, 1995).

Nowadays, sleep analyses combine EEG signals with the recording of muscle tone variations (electromyogram [EMG]; measures skeletal muscle activity) and eye movements (electrooculogram [EOG]; measures eye movement activities). This is referred to as a polysomnogram (PSG) and in humans is often complemented with other basic physiological parameters such as heart rate (electrocardiogram), oximetry, respiration, and blood pressure that are heavily and specifically influenced by sleep and wake (Roebuck et al., 2014).

During wakefulness, functional brain connectivity is high and the EEG displays irregular low-voltage fast waves, described as “desynchronized.” In contrast, during NREM sleep, connectivity within the brain is restricted and the EEG features high-voltage slow waves reflecting cortical and thalamic neural oscillations that occur relatively synchronously. Finally, REM sleep is characterized by a desynchronized EEG with low-voltage fast waves coupled with muscle atonia (loss of skeletal muscle tone) and rapid saccadic eye movements. REM sleep is also called “paradoxical sleep” because while the EEG is reminiscent of wakefulness, the absence of muscle tone is specific to sleep (M. Jouvet, Michel, & Courjon, 1959) (Fig. 1).

Effect of Sleep Loss on Pain

Figure 1. Traces of polysomnographic recordings illustrating wake, NREM sleep, and REM sleep in humans (a) and rodents (b). PSG is performed with transdermal electrodes in humans (a) and epidural electrodes in rodents (b). In both species, wake is characterized by low-amplitude, high-frequency EEG (blue line) coupled with motor activity detected in the EMG (black line). NREM sleep has three distinct stages in humans: N1, N2, and N3 and a single stage in rodents characterized by high-amplitude, low-frequency EEG and no EMG activity. REM sleep, also known as paradoxical sleep, displays low-amplitude, high-frequency EEG waves and complete muscle atonia. For (a) EEG and EMG traces courtesy of the Johns Hopkins Center for Interdisciplinary Sleep Research and Education.

Measuring Sleep

In humans, NREM and REM sleep states occur in predictable cycles in normal sleeping adults. A typical sleep cycle lasts 90 minutes and is characterized by the movement through progressively deeper “stages” of NREM (N1, N2, and N3, respectively), followed by the advent of REM sleep. Slow wave oscillations (stage N3) are predominant through the first several sleep cycles, eventually yielding to higher frequency oscillations and longer REM stages as sleep pressure declines. On average, a night’s sleep consists of four to five consecutive sleep cycles and can be visualized on a hypnogram (Fig. 2a). PSGs provide quantifiable estimates of sleep macrostructure and can be evaluated relative to clinical populations of interest. In addition to the macrostructure, measures of sleep continuity can be used to distinguish “normal sleep” from disordered sleep. In humans, sleep continuity measures principally comprise the sleep onset latency (SOL), the amount of wake after sleep onset (WASO), the total sleep time (TST), and an index of sleep efficiency (SE), which is calculated as the percent of the total sleep opportunity period spent asleep. Normal sleep is commonly thought to involve between 6.5 and 9 hours of TST, less than 30 minutes of SOL and WASO, and SE greater than 85% (Carskadon & Dement, 2005) (Fig. 2b).

Effect of Sleep Loss on Pain

Figure 2. Hypnograms and key sleep parameters analyzed in humans (a) and mice (b). Humans have consolidated sleep with more NREM sleep, especially N3, at the beginning on the night and a progressive increase in REM sleep throughout the night. Sleep continuity can be assessed by measuring onset sleep latency (SOL (1)), total amount of wake after sleep onset (WASO (2)), total sleep time (TST), and sleep efficiency (SE). Normal values are indicated in brackets. In addition to these parameters, sleep analyses can include EKG, oximetry, actigraphy, and questionnaires the next day. Mice display a polyphasic sleep, but with a similar architecture as illustrated in hypnogram of light period. Fast-Fourier transformation (FFT) of EEG signal allows spectral analyses for specific EEG frequencies, which reveals distinct patterns based on sleep wake patterns, or specific behavioral states.

While PSG provides objective assessment of sleep continuity with high temporal resolution and great reliability, the equipment and laboratory settings needed for PSG recordings are burdensome and require overnight stays in a dedicated environment, which means that data are rarely recorded for more than one or two nights. Sleep continuity can be strongly influenced by environmental (e.g., light and noise) and psychosocial factors (e.g., stress and anxiety) that would require habituation periods with extended recording sessions. Unfortunately, due to cost and logistic limitations, such longitudinal experiments are not realistically conceivable with PSG in humans. To circumvent this, sleep continuity can be inferred from analysis of activity counts derived from wrist-worn actigraphic devices or subjectively ascertained from self-reported sleep diaries. These approaches allow monitoring over multiple contiguous nights in a naturalistic environment are considered a reliable proxy for sleep continuity analyses (Carney et al., 2012; Sadeh, 2011; Smith et al., 2018). These self-report instruments have demonstrated reliability and validity, supporting their widespread dissemination in clinical contexts. These include, but are not limited to, the Pittsburgh Sleep Quality Index (PSQI) (Buysse, Reynolds III, Monk, Berman, & Kupfer, 1989), the Insomnia Severity Index (ISI) (Bastien, Vallières, & Morin, 2001), and the Epworth Sleepiness Scale (ESS) (Johns, 1991). These questionnaires often measure traits that are consequences of specific sleep disorders. With the advent of new portable technologies, ambulatory PSG should allow for the combination of the precision and objective measures of EEG recordings during sleep with the self-reported assessments from subjects or patients.

A work group commissioned by the American Academy of Sleep Medicine developed a set of research diagnostic criteria (RDC) to distinguish “normal sleepers” from individuals with insomnia (Edinger et al., 2004). These criteria have become extremely useful in developing inclusion and exclusion criteria for sleep-related research studies, because they can be assessed via clinical interview. The RDC for normal sleepers as defined by Edinger et al. (2004) are as follows: (a) the individual has no complaints of sleep disturbance or daytime symptoms attributable to unsatisfactory sleep; (b) the individual has a routine standard sleep/wake schedule characterized by regular bedtimes and rising times; (c) there is no evidence of a sleep-disruptive medical or mental disorder; (d) there is no evidence of sleep disruption due to a substance exposure, use, abuse, or withdrawal; (e) there is no evidence of a primary sleep disorder (e.g., primary insomnia, sleep apnea).

In preclinical settings, the method of choice is chronic implantation of EEG and EMG electrodes: Rodent EEG signals are recorded at the surface of the brain by implanting epidural electrodes over cortical areas overlaying the dorsal hippocampus (Fig. 1b). They are coupled with EMG recordings of the neck extensor muscles and often video monitoring (Fig. 1b). This allows for recording behavioral states for long periods of time over the course of several months. General locomotor activity can be used as a proxy for gross sleep-wake behaviors; however, this readout is limited as it cannot distinguish NREM from REM sleep. The temporal distribution of the three behavioral states (wake, NREM sleep, and REM sleep) is visualized on the hypnogram (Fig. 2b), where the polyphasic pattern of sleep-wake states in mice is evident. In addition to sleep macrostructure, sleep continuity can be evaluated in rodents by analyzing the episode number and length for wake, NREM and REM sleep, as well as the occurrence of brief awakenings (2–16 seconds) from sleep as an index of sleep fragmentation (Lena et al., 2004; I. Tobler, Deboer, & Fischer, 1997). Sleepiness can be assessed by calculating the latency to fall asleep after a specific behavioral challenge.

Behavioral states can be further characterized by analyzing brain oscillations, the relevant EEG frequency range being usually from 0.1 to 100 Hz (Niedermeyer, 2005). From low to high frequencies, we can distinguish five main EEG activity bands: delta, also called slow waves (0.5–4 Hz in humans and mice), theta (4–8 Hz in humans; 5–9 Hz in mice), sigma (8–13 Hz in humans, 10–15 Hz in mice), beta (15–30 Hz), and gamma (30–100 Hz).

NREM sleep intensity can be assessed by quantifying the EEG power within the delta range (Fig. 2d), also known as slow-wave activity (SWA): the higher the amplitude of slow waves, the deeper NREM sleep is. Consequently SWA is highest at the beginning of the night or sleep period, when the need for recuperation is the greatest, and declines exponentially as the sleep pressure dissipates (Borbely, 1982; Borbely & Achermann, 1999). SWA increases with wakefulness duration, and a dramatic increase in SWA can be observed during sleep recovery following sleep deprivation or extended wakefulness (I. Tobler & Borbely, 1986), and thus provides a quantifiable index of sleep pressure.

REM sleep, characterized by a desynchronized EEG with low-voltage fast waves (prominently theta waves; Fig. 2d), is also homeostatically regulated; that is, REM sleep pressure accumulates in its absence (during both wake and NREM sleep). However, its homeostasis is independent from NREM sleep homeostasis in rodents and humans (Endo et al., 1998; Endo, Schwierin, Borbély, & Tobler, 1997), and REM sleep deprivation is principally compensated by an increase in REM sleep amount proportional to the incurred loss (Franken, 2002).

Despite the differences in sleep-wake patterns between humans and rodents, their numerous shared features, including the NREM/REM sleep characteristics and the sleep homeostatic response, have made rodent sleep studies fundamental to basic and preclinical sleep research.

Effects of Experimental Sleep Disturbance on Nociception and Pain

While ample clinical evidence indicates an interaction between sleep disorders and pain complaints, the exact nature of this interaction has remained mostly elusive. Both sleep and pain can be heavily influenced by genetic and environmental factors, making it extremely complex to determine precise causality. To better understand how sleep affects pain, several protocols have been developed to actively prevent the entry into sleep, leading to prolonged and enforced wakefulness and the building up of sleep pressure.

Sleep Deprivation Protocols in Humans and Rodents

Human experimental models of sleep loss–induced hyperalgesia have typically taken the form of total sleep deprivation (TSD), partial sleep deprivation (PSD), and selective sleep stage deprivation (e.g., REM sleep deprivation). TSD designs involve wake periods that are maintained for at least one night, typically 24–36 hours. PSD designs often take the form of restricted sleep, whereby lights out will be delayed for a fixed period (e.g., 4 hours after a subject’s typical bedtime), though the timing of the sleep deprivation periods may vary between studies. Selective sleep stage deprivation involves explicit deprivation of one or more sleep stages, either through frank awakenings, auditory stimuli, or pharmacological manipulations. For example, both REM and NREM sleep may be interrupted in real time based on polysomnographic evidence being actively monitored by a sleep technician (Arima et al., 2001; T. Roehrs, Hyde, Blaisdell, Greenwald, & Roth, 2006). Alternatively, REM sleep can be abolished via pharmacological manipulations, such as the administration of clonidine, without altering total sleep time (Chouchou, Chauny, Rainville, & Lavigne, 2015). Sleep deprivation protocols are optimally employed in a randomized, within-subject, cross-over design, in which outcome measurements are obtained following both normal sleep and sleep deprivation in the same subject. Importantly, the effect of experimental sleep loss on central pain processing may not be unique to acute deprivation and more protocols are being designed to subject individuals to chronic sleep deprivations and determine the consequences on pain (Haack, Sanchez, & Mullington, 2007; Simpson, Scott-Sutherland, Gautam, Sethna, & Haack, 2018).

In rodents, most early work focused on the effects of “selective” REM sleep deprivation (REMSD) on pain sensitivity using various “platform-over-water” methods (D. Jouvet, Vimont, & Delorme, 1964). The single-platform technique takes advantage of the muscle atonia occurring during REM sleep by placing the animals on top of a small platform surrounded by water (Mendelson, Guthrie, Frederick, & Wyatt, 1974) (Fig. 3). As rats or mice enter REM sleep, they lose postural tone and fall into the water, causing them to wake up (cats subjected to REMSD wake up but do not fall into water). Overall, this method introduces numerous confounding factors such as isolation, wetness and potential hypothermia, movement restriction, muscle fatigue, and stress (Coenen & Van Luijtelaar, 1985; Suchecki, Lobo, Hipolide, & Tufik, 1998). Thus, a modification of this paradigm was introduced to circumvent isolation and movement restriction by allowing a socially stable group of animals (usually five) to be sleep deprived together in a large tank containing multiple small platforms (Coenen & Van Luijtelaar, 1985). Both methods fully eliminate REM sleep, but also significantly reduce NREM sleep by ~30–50% (Grahnstedt & Ursin, 1985; Machado, Hipolide, Benedito-Silva, & Tufik, 2004), and therefore cannot be considered strictly specific to REM sleep (Fig. 3a).

Effect of Sleep Loss on Pain

Figure 3. Forced locomotor activity protocols for sleep deprivation in rodents. (a) Inversed pot flower technique. Rodents stand on a single or multiple narrow platform(s). When the animal enters REM sleep, there is atonia and it falls into water (except cats). Upon waking up, animals return to the platform to eventually resume sleep. This protocol abolishes REM sleep and reduces NREM sleep by ~30%. (b) Rotating bar technique. The frequency and velocity for the bar movement are adjustable. Upon contact, animals wake and move/climb the bar. (c) Wheels or treadmills. Upon activation, animals are forced to walk, thereby preventing them from sleeping.

Forced locomotor activity can also prevent animals from sleeping and can be achieved by placing animals on automated treadmills, cylinders/drums, or running wheels that are continuously in motion at a very slow pace during the sleep deprivation period, eliminating nearly all sleep (Friedman, Bergmann, & Rechtschaffen, 1979; Kim, Laposky, Bergmann, & Turek, 2007; Lancel & Kerkhof, 1989). Additional control groups are needed to account for locomotor activity and are designed to produce the same absolute amount of movements without significant sleep loss. Less intense methods consist of circular cages equipped with a rotating sweeping bar or cage floor programmed to rotate/move at specific intervals and durations (Ringgold, Barf, George, Sutton, & Opp, 2013) (Fig. 3b). For example, motion is triggered for 10 seconds followed by 60 seconds of inactivity (Ringgold et al., 2013; Sutton & Opp, 2014). Such protocols are better labeled sleep fragmentation than sleep deprivation, as they do not significantly reduce NREM sleep or cause a compensatory rebound, but rather dramatically disrupt NREM sleep episodes and consequently nearly suppress REM sleep. While these techniques can be applied for long periods of time and are less stressful than the platform methods, notably by reducing social isolation (Leenaars et al., 2011), they are still associated with a moderate increase in corticosterone levels (Ringgold et al., 2013).

Recently, researchers developed techniques to improve the translational value of sleep deprivation protocols by sleep-depriving animals (NREM + REM sleep) only during a portion of the rest period but over several days, in a minimally stressful manner, to mimic modern lifestyles. To some extent, these types of sleep manipulations resemble more closely experimental human studies or the type of sleep disturbance observed in the general population. The most widely used manual method to perform total sleep deprivation is the “gentle handling” technique where the animal is provided with a novel object such as a piece of paper or nesting material to keep it active (Franken, Dijk, Tobler, & Borbely, 1991). While historically gentle contact or even direct handling of the animal was possible when sleep pressure was becoming too high, recent studies have favored strategies to avoid any direct contact and instead promote extended wakefulness by providing a whole battery of novel objects optimized for rodents’ attention throughout the sleep deprivation protocol (Alexandre et al., 2017) (Fig. 4a). Only one object is present at a single time in the cage with the animal, and as soon as an attempt to sleep occurs, a novel object is provided to incite chewing, which is an innate nonstressful behavior in rodents. Such protocol can be performed for acute (6 to 12 hours) or chronic (6 hours per day for 5 days) sleep deprivation with no stress. It reduces NREM sleep by 95–99% and fully abolishes REM sleep (Alexandre et al., 2017).

Effect of Sleep Loss on Pain

Figure 4. Minimally stressful sleep deprivation protocols. (a) Gentle “handling” technique. Mice are monitored for sleep attempts by EEG/EMG. When the animal tries to fall asleep, an object is provided to incite its exploration/activity. Only one object is present at a single time in the cage and the animal is never directly touched to avoid stress. Repeating this protocol over several days will cause a build-up in sleepiness and sleep pressure, despite a normal sleep rebound during recovery periods. (b) New protocols couple EEG machine learning to detect NREM sleep or REM sleep and automatically trigger a brief movement of the cage to wake up the animal.

With the advent of machine-learning technologies, protocols are being developed to allow automatic sleep interruptions based on real-time EEG/EMG signals. The stimulation to wake up the animal (from NREM or REM sleep) can be a brief shake/upward motion (Libourel, Corneyllie, Luppi, Chouvet, & Gervasoni, 2015) or rotation (a few seconds) of the cage floor, with minimal stress (Alexandre et al., 2017). While these new techniques are extremely effective at disrupting sleep (sleep fragmentation) or selectively inhibiting REM sleep (Chauveau et al., 2014; Libourel et al., 2015; Ringgold et al., 2013), they often are unable to achieve satisfactory levels of total sleep deprivation over long periods of time, as the animals habituate rapidly and find a way to sleep through or in between the automated interventions. A combination of both automated stimulation based on EEG/EMG feedback and behaviorally engaging activities would be the best option to successfully achieve total chronic sleep deprivation while minimizing the time and labor for the experimenters.

Sleep Deprivation Increases Pain Responses

Numerous experimental studies have investigated the impact of experimental sleep disturbance on pain perception (Finan, Goodin, & Smith, 2013; Lautenbacher, Kundermann, & Krieg, 2006; Moldofsky, 2001; Schrimpf et al., 2015), and despite highly heterogeneous sleep disruption protocols, the overall result points to an increase in pain responses and behaviors when sleep is disturbed in otherwise healthy humans, rats, or mice (Fig. 5).

Effect of Sleep Loss on Pain

Figure 5. Effects of total sleep loss or REM sleep on pain in humans, rats, and mice for mechanical, thermal, chemical, and spontaneous pain. Red arrow indicates increased pain, green equal sign indicates no changes after sleep loss, and N.D. indicates “not determined.” For cold pain threshold, the temperature of the thermoprobe used is indicated. (a) REMSD controlled by PSG, which indicated a slight loss of NREMS N2. (b) REMSD controlled by PSG, which indicated a slight increase in NREMS N2. (c) Sleep fragmentation protocol that caused 50% REM sleep loss but no change in NREMS amount. In all other so-called REMSD protocols, there is about ~30% NREM sleep loss.

One fundamental question researchers explored was whether hyperalgesia caused by lack of sleep is stage specific; in other words, is one type of sleep necessary for normal pain sensitivity but not another. Almost all REMSD experiments performed in rodents using the platform techniques were associated with an increase in nociceptive behaviors, in particular mechanical and thermal hypersensitivity (Fig. 5). However, because these protocols also cause a significant reduction in NREM sleep and an increase in stress levels, it is difficult to conclude from these studies that loss of REM sleep alone is hyperalgesic. In humans, where REM sleep deprivation can be achieved without major NREM sleep deficit (as ascertained with PSG analyses), no increase in pain responses was observed (Azevedo et al., 2011; Moldofsky & Scarisbrick, 1976). In addition, sleep fragmentation protocols designed to disrupt NREM sleep (without decreasing its total duration) also decreased REM sleep significantly (by at least ~50%), without producing hyperalgesia in mice (Alexandre et al., 2017). Together, these findings argue against a specific role for REM sleep loss in causing pain hypersensitivity. In humans it is possible to specifically prevent slow-wave sleep (stage N3) using sound pulses. Slow-wave sleep deprivation was reported hyperalgesic in some studies (Lentz, Landis, Rothermel, & Shaver, 1999; Moldofsky & Scarisbrick, 1976; Onen, Alloui, Gross, Eschallier, & Dubray, 2001) but not others (Arima et al., 2001; Older et al., 1998). These discrepancies might be attributable to differences in methodologies employed and pain modalities tested, which prevents proper cross-analyses to determine to what extent lack of slow-wave sleep contributes to pain hypersensitivity. Unfortunately it is not possible to prevent only NREM sleep in rodents without dramatically impacting REM sleep because of the organization of NREM-REM sleep cycles.

In contrast, substantial total sleep (NREM + REM sleep) deprivation is almost always associated with a significant increase in pain sensitivity, and this is consistent across species (Alexandre et al., 2017; Moldofsky, 2001; Onen, Alloui, Eschalier, & Dubray, 2000) (Fig. 5).

But does a general lack of sleep affect similarly all types of pain modalities? Historically pain assays have differed greatly between humans and rodents, with the majority of human pain assays focusing on questionnaires, pressure pain, and thermal blocks, while in rodents and especially mice, pain assessment relied mostly on punctate mechanical pain (von Frey filaments, calibrated forceps) and contact heat (hotplate). However, recent studies have started to bridge these gaps, allowing a better cross-species analysis and emphasizing a consistent hyperalgesic effect of sleep loss among species (Fig. 5), with the major limitation of assessing spontaneous pain or general body aches in rodents.

Sleep loss consistently increases mechanical pain in humans, rats, and mice (Fig. 5). Pressure pain, assessed by an algometer or the Randall and Sellito test, is increased after a single night of sleep loss or sleep restriction (2 hours of sleep) in humans (Faraut et al., 2015; Schuh-Hofer et al., 2013) and after 24 hours of REMSD in rats (Sardi, Tobaldini, Morais, & Fischer, 2018). Punctate mechanical pain, which is milder than pressure pain and usually assessed with von Frey filaments, is also enhanced after acute total sleep deprivation in humans (Schuh-Hofer et al., 2013), rats (Wodarski et al., 2015), and mice (Alexandre et al., 2017). Pinprick-induced pain sensation is amplified in humans after a single night of total sleep deprivation (Matre et al., 2015; Schuh-Hofer et al., 2013), but it has not been assessed in rodents yet.

For heat pain sensitivity, the vast majority of studies have reported increased pain responses (and decreased pain threshold) in humans (Azevedo et al., 2011; T. Roehrs et al., 2006; Schuh-Hofer, Baumgartner, & Treede, 2015; Schuh-Hofer et al., 2013; Tiede et al., 2010), rats (Vanini, 2016; Wodarski et al., 2015), and mice (Alexandre et al., 2017). In humans, most assessments rely on the decision of the subject to describe pain (when and its intensity), while in rodents most assays measure the latency to cause a reflex withdrawal, which likely represents a reaction trigger by reaching a higher pain threshold. However, the development of operant pain assays in rodents (where the animal chose where to go based on temperature) can now mimic more closely the human tests (Alexandre et al., 2017; Harvey et al., 2010). The effects of sleep deprivation on these operant pain assays also indicated exacerbated heat pain sensitivity (Alexandre et al., 2017).

Cold pain assessment is extremely complex and the several readouts that can be obtained do not necessarily reflect the same biological phenomena. Cold pain threshold is determined in humans by applying a thermoprobe set at 4°C at the surface of the skin and measure the time to cause pain or the intensity of the pain sensation elicited. In rodents the main techniques consist of exposing animals to cold (typically a plate set at 5°C or a drop of acetone that cools the skin to 4°C for 1 second) and measuring the avoidance or nociceptive-type reflexes (flinches of the paw). Total sleep deprivation does not seem to cause a major change in cold pain threshold or ratings upon acute exposure in humans (Faraut et al., 2011; Sauvet et al., 2012; Schuh-Hofer et al., 2013) or mice (Alexandre et al., 2017). In rats, cold avoidance was tested using a thermal place aversion apparatus with plates set at 1°C and 45°C. REMSD decreased in time spent at 1°C, suggesting cold aversion (Harvey et al., 2010). However, sleep deprivation also causes a thermal place preference toward warmer (yet innocuous) areas (Alexandre et al., 2017), which could contribute to the reduced time spent at 1°C. Because the skin takes a few seconds to change temperature in contact with warmer or colder areas, the actual temperature of the skin of rats oscillating between 1°C and 45°C plates would be relevant to assess to better understand their thermal aversion or preference. Noxious cold can also be used to assess (cold) pain tolerance. Total sleep deprivation reduces the ability to sustain a painful cold stimulus in humans (Larson & Carter, 2016; Simpson et al., 2018), an effect thought to be caused by a defect in central processing that involves the diffuse noxious inhibitory controls (DNIC), measured with conditioned pain modulation (M. T. Smith, Edwards, McCann, & Haythornthwaite, 2007) (CPM). To date, DNIC alterations have not been studied coupled with behavioral analyses in rodents in the context of sleep and pain. However, a similar increase in pain responses upon exposure to sustained noxious stimuli is observed in sleep-deprived rats and mice when administrated chemical irritants such as capsaicin, formalin, or acetic acid (Alexandre et al., 2017; Tomim et al., 2016; Yaoita et al., 2018), which could reflect a reduced tolerance to pain, or at least some shared mechanisms.

Interestingly, both the decrease in pain tolerance and the increase in capsaicin-induced pain responses are stronger in females than males (Alexandre et al., 2017; Eichhorn, Treede, & Schuh-Hofer, 2018), which could suggest that sleep deprivation causes a more severe loss of descending inhibitory controls in females than males (M. Smith et al., 2019) and highlight an important gender difference in how sleep affects pain sensitivity. A 2007 study employing three nights of sleep disruption in healthy women introduced the possibility that insufficient sleep may impair central pain processing via impaired conditioned pain modulation (M. T. Smith et al., 2007). Several studies have followed up on that initial finding, uncovering sex differences. A single night of sleep restriction impaired conditioned pain modulation in females but not in males (Eichhorn et al., 2018). Sex differences in central pain processing were also observed in another recent sleep disruption study, with females, but not males, evidencing increased temporal summation and males, but not females, evidencing increased secondary hyperalgesia (Iacovides, George, Kamerman, & Baker, 2017; M. Smith et al., 2019). The study showed that repeated nights of sleep disruption decreased habituation to a tonic ischemic pain stimulus in healthy women. Together, these findings generally corroborate cross-sectional data, which have suggested there may be sex differences in the extent to which sleep disturbance increases pain sensitivity (Bulls et al., 2015; Petrov et al., 2015).

Lastly, spontaneous pain complaints (general body pain, low back pain, or headache/migraine) remained unchanged after a single night of sleep deprivation or restriction (Schuh-Hofer et al., 2013; M. T. Smith et al., 2007), but increased after several days of chronic sleep restriction (Busch et al., 2012; Haack et al., 2007; Schey et al., 2007), alongside elevated levels of prostaglandins (Haack, Lee, Cohen, & Mullington, 2009), which are often associated with headaches and migraines. Remarkably, insufficient sleep has been found to be a major trigger for migraines (Houle et al., 2012; Palma, Urrestarazu, & Iriarte, 2013).

Altogether, these experiments indicate that despite the great heterogeneity of pain readouts, acute total sleep loss increases pain sensitivity across several species. Interestingly, there is a positive “dose-dependent” association between the duration of acute total sleep deprivation and the intensity of hyperalgesia: the greater the sleep lost, the greater the pain hypersensitivity, and this holds true for several pain modalities (mechanical, thermal) in both humans and mice (Alexandre et al., 2017; T. Roehrs et al., 2006).

While the duration of sleep loss determines the magnitude and extent of the resulting hyperalgesia under acute conditions, the timing, as well as the potential recurrence of insufficient sleep, adds another layer of complexity. Experimental protocols of chronic sleep restriction, sometimes called partial sleep deprivation, where sleep is limited to a just a few hours (2 to 6 hours) for several days greatly impact pain sensitivity. While a single night of restricted sleep (4 hours) (Schestatsky et al., 2013; Schey et al., 2007; M. T. Smith et al., 2007; Tiede et al., 2010) did not necessarily affect “spontaneous” pain, chronic sleep restriction increased pain complaints and responses in all studies (Ablin et al., 2013; Haack & Mullington, 2005; Haack et al., 2007). A recent study exposed healthy adults to a chronic sleep restriction protocol consisting of 3 weeks in which sleep was restricted to 4 hours on 5 nights of each week, and allowed to recover on 2 nights each week (Simpson et al., 2018). Compared to controls who slept normally in the laboratory over a 3-week period, the chronic restriction group showed decreased habituation to cold pain and increased temporal summation. These results suggest that central pain processes are altered not only in response to acute and powerful sleep deprivation, but also to chronically insufficient sleep, lending ecological validity to the broader hypothesis that sleep loss disrupts central pain modulatory networks.

In mice, 6 hours of sleep deprivation were not sufficient to alter pain responses acutely, but when repeated daily over 5 days, this moderate sleep restriction led to a gradual increase in thermal and mechanical pain sensitivity (Alexandre et al., 2017), despite observing normal homeostatic sleep response (i.e., increases in SWA and sleep amount) during each sleep opportunity. This build-up in pain hypersensitivity was concomitant with an increase in sleepiness, suggesting that pain perception is highly sensitive to levels of alertness. Intriguingly, chronic sleep deficiency does not affect all pain modalities with the same timing, indicating that specific mechanisms might be involved with different possible clinical implications. Similarly, in rats subjected to chronic sleep restriction (6 hours daily for 26 consecutive days), pressure pain hypersensitivity was significant on the third day and increased until day 12, where it reached a plateau (Sardi, Lazzarim, et al., 2018). The gradual development of hyperalgesia (and neurobehavioral deficits) during chronic sleep restriction protocols, even when sleep recovery periods are allowed and normal homeostatic sleep response occurred (Alexandre et al., 2017; S. Banks et al., 2010), suggests a mechanism sensitive to excessive wakefulness, that is, a maximum period beyond which normal pain perception and neurobehavioral functioning cannot be maintained (Van Dongen et al., 2003).

Finally, recent studies have shown that extending sleep opportunities in subjects chronically sleep restricted can have beneficial effects on both sleep and pain sensitivity (Faraut et al., 2011; T. A. Roehrs, Harris, Randall, & Roth, 2012; Simonelli et al., 2019). Extending sleep by only 1.8 hours per night in a group of mildly, chronically sleep-deprived volunteers not only increased measures of daytime alertness but also reduced heat pain sensitivity (T. A. Roehrs et al., 2012). Remarkably, the magnitude of the reduction in pain sensitivity was greater than the effect produced by 60 mg of codeine (Steinmiller et al., 2010). Napping (two 30-minute naps, morning and afternoon) was also shown to alleviate pain hypersensitivity caused by chronic sleep restriction (Faraut et al., 2011). Lastly, extending sleep in healthy normal sleepers for 2 hours per night over 5 nights significantly increased pain tolerance (but not threshold) (Simonelli et al., 2019). Even more, those who felt they needed more sleep than they were getting in their daily lives prior to entering the experiment experienced the greatest increase in pain tolerance following the sleep extension period. A natural and understandable conclusion of this study and the many studies that have demonstrated a temporal precedence of sleep disturbance over pain is that sleep should be a viable target of interventions aiming to improve pain management.

Sleep Loss Increases Sensitivity to Pain but Not to Other Sensory Modalities

One important question raised by the finding that insufficient sleep enhances pain sensitivity is the matter of general responsiveness to sensory stimuli after sleep loss. Surprisingly, there is relatively little research focusing on how sleep loss affects sensory and perceptual processes (Killgore, 2010). While sleep loss increases the sensitivity and responses to noxious stimuli, this is not the case for innocuous stimuli. Responsivity to light mechanical stimuli such as low-pressure von Frey filaments or a gentle stroke with a paint brush (that do not cause activation of nociceptors) is not changed by sleep loss either in humans (Schuh-Hofer et al., 2013) or mice (Alexandre et al., 2017). Innocuous thermal discrimination is also maintained after total sleep deprivation in humans (Kundermann, Spernal, Huber, Krieg, & Lautenbacher, 2004; Schuh-Hofer et al., 2013); however, subjects often report feeling cold despite a constant room temperature (Schuh-Hofer et al., 2013). In rodents, thermal preference can be assessed by an operant test where animals walk on a thermal gradient (5°C to 55°C) and decide at which temperature they prefer to stay (Moqrich et al., 2005). Somewhat similar to humans, sleep-deprived mice show a preference toward slightly warmer areas to settle (Alexandre et al., 2017). Interestingly, in the same assay sleep loss strongly enhances the avoidance for noxious heat (41°C) despite the animals seeking warmer temperatures, which suggests that distinct neural pathways are involved (Alexandre et al., 2017).

Auditory and visual acuities do not appear to be affected by sleep loss (Alexandre et al., 2017; Franzen, Buysse, Dahl, Thompson, & Siegle, 2009; Scherer, Claro, & Heaton, 2013). However, sleep deprivation impairs several downstream cascades of these systems such as the amplitude of the jump/startle upon exposure to a loud sound (Alexandre et al., 2017), the reaction time (for visual but not auditory responses; Alexandre et al., 2017; Jung, Ronda, Czeisler, & Wright, 2011), the adequateness of the response (Jung et al., 2011; Liberalesso et al., 2012), or autonomic reflexes associated with visual input (Franzen et al., 2009). These defects then are not due to an impairment of the perception of visual and auditory stimuli, but rather they are an indirect consequence of fatigue (reduced locomotor responses) and altered central nervous system (CNS) processing caused by the reduced alertness after sleep loss.

The overall effects of lack of sleep on sensory systems appear quite similar in humans and rodents and indicate that sleep loss causes a specific increase in pain sensitivity, but not a general state of sensory hyperresponsiveness.

Sleep Deprivation Exacerbates Existing Pain Conditions

A growing body of evidence indicates that insufficient sleep worsens existing pain and may be a significant risk factor for developing persistent pain. Longitudinal studies characterizing the temporal dynamics between sleep and pain were first reviewed in 2004 by Smith and Haythornthwaite (M. Smith & Haythornthwaite, 2004) and updated in 2013 by Finan et al. (2013). Over the past two decades, macrolongitudinal (e.g., epidemiological) and microlongitudinal (e.g., daily process) studies have largely supported the notion that there is a bidirectional relationship between sleep and pain. There appears to be more consistent evidence that the temporal effect of sleep on pain is stronger than that of pain on sleep (Finan et al., 2013), though a systematic review on this topic has yet to be conducted. Nonetheless, the interest in unraveling the temporal dynamics between sleep and pain continues to unfold, as evidenced by two recent review articles principally focused on this aspect of the sleep-pain link (Afolalu, Ramlee, & Tang, 2018; Andersen et al., 2018) and a plethora of longitudinal studies published in the last 3 years (Bromberg, Connelly, Anthony, Gil, & Schanberg, 2016; T.-Y. Chen et al., 2018; Dunietz et al., 2018; Fisher et al., 2018; Generaal, Vogelzangs, Penninx, & Dekker, 2017; Gerhart et al., 2016; Koffel, Krebs, Arbisi, Erbes, & Polusny, 2016; Landmark et al., 2018; Miller et al., 2018; Rabbitts, Zhou, Narayanan, & Palermo, 2017; Ravyts et al., 2018; Sanders et al., 2016; Stocks et al., 2018).

Epidemiological studies have continued to support the “bidirectional” hypothesis. Chen and colleagues offered the first data on this topic in an Asian sample, analyzing longitudinal data from large epidemiological surveys among older adults in Singapore (N = 2,111) and Japan (N = 2,888) (T.-Y. Chen et al., 2018). Short sleep duration (<6 hours) at baseline predicted new pain onset, and any pain at baseline predicted the new onset of short sleep duration, both at 2-year and 3-year follow-up time points. In a large sample of older adults (N = 2,239), difficulties initiating or maintaining sleep at baseline increased the odds of developing incident pain by 24% and 28%, respectively (Dunietz et al., 2018). Moreover, anxiety symptoms accounted for 17% of the variance in that prospective association, providing support for the theoretical framework that the link between insomnia and pain may be perpetuated by hyperarousal (Finan & Smith, 2013; Smith, Perlis, Smith, Giles, & Carmody, 2000). In a similar prospective analysis of 2,737 TMD-free adults, poor sleep quality predicted the onset of TMD, and this effect was mediated by perceived stress (Sanders et al., 2016). In a prospective study of Norwegian adults (Landmark et al., 2018), the degree to which individuals endorsed having trouble sleeping at baseline predicted both incident chronic pain among those who were pain-free at baseline (N = 1,770) and worsening pain among those with chronic pain at baseline (N = 1,789).

Longitudinal bidirectional effects have also been reported in recent studies with shorter time scales. Stocks et al. found that sleep disturbance and neuropathic joint pain are prospectively and bidirectionally related in patients with osteoarthritis who have undergone joint replacement surgery (Stocks et al., 2018). In a recent daily diary study, the variability of pain, but not the average pain level, of older adults was associated with sleep continuity (Ravyts et al., 2018). Although the authors did not examine the opposite directional effect of sleep on pain, the findings may help explain the previously reported weak/inconsistent prospective association of pain on sleep, which has principally been evaluated from the standpoint of pain level rather than variability over time. Pakpour et al. (2018) analyzed longitudinal outcome data among patients with chronic low back pain and found that both pre-existing sleep problems and the development of sleep problems over time significantly decreased the likelihood of pain symptom resolution by 6-month follow-up, whereas the resolution of sleep problems over time increased the likelihood of pain symptom resolution (Pakpour, Yaghoubidoust, & Campbell, 2018).

In support of these longitudinal observations, several studies have investigated the consequences of experimental sleep deprivation prior to body insult in rodent models of inflammatory, postoperative, chemotherapy-induced, and neuropathic pain.

Total sleep deprivation carried out for 9 hours immediately prior to an intraplantar injection of formalin (5%) in rats caused an exacerbated mechanical hypersensitivity (but somehow protects against thermal pain hypersensitivity) that lasted up to 3 weeks, compared to non-sleep-deprived animals also injected with formalin (Vanini, 2016).

Preoperative sleep disturbance strongly predicts the severity and/or persistence of pain hypersensitivity in a clinically relevant model of postoperative pain by intraplantar incision and muscle distension in rats (Brennan, Vandermeulen, & Gebhart, 1996). Subjecting rats to 24 hours of REMSD (~30% NREM sleep loss) before plantar incision of the hind paw worsened both punctate mechanical hypersensitivity (von Frey) and guarding behavior, and it delayed recovery compared to operated non-sleep-deprived animals (Xue et al., 2018). Intermittent REMSD (6 hours daily for 3 consecutive days; estimated 2 hours of NREM sleep lost) applied just before or immediately after hind paw plantar incision did not affect the degree of mechanical and thermal allodynia but delayed recovery (P. K. Wang et al., 2015). Acute total sleep deprivation carried out for 6 hours immediately before incision surgery increased the intensity of tactile allodynia and prolonged recovery time compared to non-sleep-deprived animals (Hambrecht-Wiedbusch et al., 2017). Whereas the effect on pain severity showed some discrepancies that can be attributable to different methodologies, a significant delayed recovery was always observed, underlying the importance of sleep in healing processes.

Paclitaxel, a chemotherapy agent commonly used to treat solid tumor cancers, is associated with axonal neuropathy that predominantly affects sensory nerves (Cavaletti & Marmiroli, 2004), and this can be duplicated in both rats and mice that develop mechanical hypersensitivity upon the agent administration (Hopkins, Duggett, & Flatters, 2016). Chronic sleep restriction (6 hours of total sleep deprivation every other day for four cycles) caused a cumulative exacerbation of paclitaxel-induced mechanical hypersensitivity throughout repeated sleep restriction (Kozachik, Opp, & Page, 2015). Sleep recovery opportunities throughout the sleep restriction protocol were not sufficient to counteract the adverse effects of sleep loss on paclitaxel-induced mechanical pain (Kozachik et al., 2015).

Finally, neuropathic pain caused by chronic constriction injury in rats is aggravated, but not precipitated, by 3 days of total sleep deprivation (using a mechanized version of the platform method that forces rats to walk for 8 seconds every 15 seconds) (Huang, Chiang, Chen, & Tsai, 2014). It is important to note, however, that behavioral assessments were performed only 7 days after the end of the preemptive sleep deprivation, so it is possible that pain hypersensitivity developed faster in sleep-deprived animals.

Sleep Loss Hyperalgesia and Analgesics

Insufficient sleep not only enhances pain sensitivity but also reduces analgesic efficacy, especially that of opioids. In rodents, this effect is observed after total sleep deprivation (Alexandre et al., 2017) and REM sleep deprivation (Nascimento, Andersen, Hipolide, Nobrega, & Tufik, 2007; Skinner, Damasceno, Gomes, & de Almeida, 2011; Tomim et al., 2016; Ukponmwan, Rupreht, & Dzoljic, 1984). In rats, 96 hours of REMSD reduces the analgesic action of morphine at low doses (2.5 and 5 mg/kg) but not at a high dose (10 mg/kg) in the hot plate test (Nascimento et al., 2007), and it has been proposed that REM sleep could be important to maintain opioid receptor responsiveness (Onen et al., 2000, 2001). However, the loss of efficacy of opioids specifically caused by REM sleep loss, without a confounding loss of NREM sleep, has not been tested yet. In any case, such loss of opioid efficacy for pain responses in sleep-deprived individuals represents a potential major risk at the clinical level where this could likely accelerate the development of tolerance, leading to dose escalation and the risk of dependence or overdose.

Interestingly, administration of the nonselective COX1/2 inhibitor ibuprofen failed to prevent both mechanical and heat hypersensitivity induced by 9 hours of total sleep deprivation in mice and rats (Alexandre et al., 2017; Wodarski et al., 2015). While it is possible that preventing the increase in prostaglandin production caused by sleep loss reduces spontaneous pain and body aches complaints (Haack et al., 2009), these results suggest that ibuprofen administration in sleep-deprived individuals will not reduce evoked pain hypersensitivity, thereby producing an apparent loss of efficacy when comparing to well-rested subjects.

Sleep Fragmentation and Pain

Alexandre and colleagues designed a protocol to fragment NREM sleep with no decrease in NREM amount and a partial loss of REM sleep (~50%) (Alexandre et al., 2017). Mice were placed in cage where an electromagnet under the cage floor moves the platform up (duration of movement: 10–20 microseconds) when an electrical signal is applied. To prevent mice from habituating to the sleep fragmentation protocol, the software generates a random arrangement of stimuli by varying stimuli intensity, number of stimuli per sequence (2–4), and time between sequences (0.5–0.9 minutes). Mice subjected to 6, 9, or 12 hours of automated sleep fragmentation over 5 consecutive days did not develop pain hypersensitivity for mechanical or heat stimuli (Alexandre et al., 2017). In addition, there was no increase in NREM sleep amount during the subsequent recovery periods. Another sleep fragmentation study in mice used an apparatus where the cage floor consisted in a motorized disc rotating for specific durations and intervals (Ringgold et al., 2013). This method produces a nonsignificant NREM sleep decrease with no compensatory rebound and a marked REM sleep reduction, and only modestly increases plasma corticosterone levels. They designed a protocol where sleep was interrupted every 30 seconds by rotations of the cage floor that lasted for 8 seconds for 12 hours a day for 5 consecutive days. Interestingly, sleep fragmentation did not alter mechanical thresholds (Sutton & Opp, 2014). However, the same chronic sleep fragmentation paradigm exacerbated pain hypersensitivity caused by intramuscular (gastrocnemius) injection of acidified saline (Sutton & Opp, 2014).

Altogether these findings indicate that NREM sleep fragmentation does not affect nociceptive pain but may be a potential risk factor of developing more severe and persistent pain.

The Case of Forced Awakenings and Pain

Another type of partial sleep deprivation is known as the forced awakenings (FA) procedure (Finan, Quartana, & Smith, 2015; M. Smith et al., 2019; M. T. Smith et al., 2007). Under this protocol, subjects are given a standardized lights-out time and permitted to fall asleep, but they are awakened repeatedly throughout the night according to a standardized and randomized pattern of awakenings, which vary in duration (e.g., 20–60 minutes). This protocol is extremely etiologically relevant to model sleep interruptions in humans (that occur frequently in various in-hospital settings). Forced awakenings decreased heat pain thresholds and diffuse noxious inhibitory controls (DNICs) after a single night (M. Smith et al., 2019; M. T. Smith et al., 2007). In addition, the FA procedure caused an increase in secondary mechanical hyperalgesia upon intradermal capsaicin administration in men only, while temporal summation caused by repeated pinprick applications is increased only in women (M. Smith et al., 2019), supporting the notion of gender-specific effects of sleep disturbances on pain sensitivity. Finally, FA lowered positive affect levels and blunted the inhibition of pain by positive affect, thus hindering the potential analgesic properties of positive bias (Finan et al., 2017).

Mechanisms of Sleep Loss–Induced Hyperalgesia: Multiple Possible Pathways

Pain is a complex, multidimensional sensation that involves sensory-discriminative, cognitive-evaluative, and affective-motivational components (Melzack & Casey, 1968; M. Smith et al., 2019). Sleep disturbance can affect all these aspects, and therefore the net result on the pain response eventually generated will vary greatly depending on the type and duration of sleep loss, the basal state of the individual (pain-free or pre-existing pain, health status, etc.) or its sleep history. In the following section, we will describe how sleep loss can enhance pain signals at the periphery, by altering the immune response and in the CNS by shifting the excitatory/inhibitory balance of the nociceptive pathways, but also centrally by altering cognitive and emotional pain processing (Haack & Mullington, 2005; Killgore, 2010; Versace, Cavallero, De Min Tona, Mozzato, & Stegagno, 2006) (Fig. 6).

Effect of Sleep Loss on Pain

Figure 6. Schematic representation of the effects of sleep loss on several pain pathways (highlighted in red). Sleep loss dysregulates the immune system, which leads to a shift toward proinflammatory responses, which in turn can increase nociceptor activation/sensitization. Sleep loss also alters several descending control systems that originate in the midbrain, pons, and medulla (see inset in green). The PAG-RVM system, critical for opioid efficacy, is inhibited in sleep-deprived animals. Inhibitory noradrenergic systems that originate from locus coeruleus are downregulated while pain-promoting CCK-expressing descending controls originating from the RVM are upregulated. SRD neurons involved in DNIC are depressed during sleep deprivation. Altogether, these changes promote pain transmission and reduce endogenous pain inhibition. Finally, sleep loss affects the emotional component of pain processing and attention through changes in the nucleus accumbens. PAG: periaqueductal gray; MOR: mu-opioid receptor; LC: locus coeruleus; RVM: rostral ventral medial medulla; RM: raphe magnus; SRD: subnucleus reticularis dorsalis; NA: noradrenaline; CCK: cholecystokinin; Gly: glycine; 5-HT: serotonin.

At the Periphery: The Immune System

Tissue injury or infection triggers a physiological response called inflammation, which is characterized by redness, swelling, increased local temperature, and pain (Chiu, von Hehn, & Woolf, 2012; Larsen & Henson, 1983). Inflammatory pain is caused both by the activation of nociceptors that can detect bacteria (Chiu et al., 2013) and by the actions of the immune system that sensitize nociceptors. Many aspects of the immune response are associated with increased pain sensitivity, from the swelling of lymph nodes where subsets of immune cells are produced to the release of proinflammatory cytokines that can diffuse from the peripheral tissues where they sensitize nociceptors (Binshtok et al., 2008; Brenn, Richter, & Schaible, 2007; Sommer & Kress, 2004) all the way to the brain where they produce fever and fatigue (sickness behavior) (Dantzer, 2004, 2018). The immune system is heavily regulated by circadian and sleep-wake cycles (Besedovsky, Lange, & Born, 2012; Dimitrov, Besedovsky, Born, & Lange, 2015; Imeri & Opp, 2009; M. R. Irwin & Opp, 2017; Lange, Dimitrov, & Born, 2010), so it is not surprising that it is affected by sleep disruption (Bryant, Trinder, & Curtis, 2004). Insufficient sleep can alter the immune response at multiple steps: production of immune cells, detection of pathogens, proliferation, recruitment and addressing of activated immune cells into relevant tissues, and the activation of specific intracellular pathways. The net effects on the immune response, and by extension on pain sensitivity, will therefore vary extensively depending on the type of immunity engaged.

Immunity has evolved into a complex and dynamic system with several subpopulations of highly specialized cells that interact to provide a fast and targeted reaction. Broadly, the immune system can be divided into two main classes: the innate immune system that corresponds to a nonspecific but immediate response upon detection of pathogens (Aderem & Ulevitch, 2000), and the adaptive immune system that relies on the prior exposure to the foreign body to develop a highly targeted cellular response (Flajnik & Kasahara, 2010). The innate immune system is formed by macrophages, monocytes, eosinophils, neutrophils, basophils, and mast cells which all originate from myeloid progenitors (found in bone marrow), as well as natural killer cells (NK cells) that originate from lymphoid progenitors. The adaptive immune system is formed by lymphocytes (T cells, B cells) that also originate from lymphoid progenitors (found in lymph nodes). T cells are further classified into helper (Th), regulator (Treg), killer (cytotoxic), and memory. T-helper cells are essential to orchestrate the type of immune response required to best fight the pathogen. It is important to note that in physiological settings, both innate and adaptive immune systems are activated during infections and many cross-talks occur throughout the inflammation process. This series of coordinated actions of both the innate and adaptive immune system is essential to produce an adequate response against infectious threats while preventing tissue damage or auto-immunity. Each immune response will consist of specific immune cells and cytokines which will have a distinct effect on pain sensitivity.

Based on the nature of the foreign body encountered, specific subsets of T cells will be predominantly activated to direct the immune reaction accordingly. The type of T cells activated characterize (and give the name to) the type of immune response that will be promoted. Bacterial infections cause an increase in Th-1 lymphocytes, which promote the activation and differentiation of macrophages and cytotoxic T cells. It is associated with the production of interferon-γ, IL-2, and IL-1β and is often referred to as the “cellular immune response.” Interferon-γ causes increases pain sensitivity (Tsuda et al., 2009), notably by reducing spinal inhibitory currents at the spinal cord level (Vikman, Hill, Backstrom, Robertson, & Kristensson, 2003). IL-1β is a major proinflammatory cytokine that binds to nociceptors to increase their excitability (Binshtok et al., 2008; Stemkowski, Noh, Chen, & Smith, 2015) and also increases spinal excitability (Samad et al., 2001), which causes pain behaviors (Binshtok et al., 2008). IL-1β triggers the induction of cyclooxygenase 2 (COX2) in macrophages but also in the spinal cord (Samad et al., 2001), further amplifying central sensitization and pain (Latremoliere & Woolf, 2009). IL-2 has antinociceptive properties, in part due to its ability to partially bind to peripheral opioid receptors (Y. Wang et al., 1996).

Parasites or allergic reactions lead to an increased production of Th-2 lymphocytes, which promotes the proliferation of antibody-producing B cells, eosinophils, and mast cells and secretion of cytokines like IL-4, IL-5, IL-6, or IL-13, and it is referred to as the “humoral immune response.” IL-6 is a key proinflammatory cytokine and a major signaling molecule both for the immune systems and neurons. IL-6 causes an increase in pain sensitivity (Kawasaki, Zhang, Cheng, & Ji, 2008) by sensitizing peripheral nociceptors (Brenn et al., 2007) and reducing spinal inhibition (Kawasaki et al., 2008). IL-5 can directly activate nociceptors (Talbot et al., 2015), suggesting a potential pronociceptive role while both IL-4 and IL-13 display anti-nociceptive properties (Hao, Mata, Glorioso, & Fink, 2006; Kiguchi et al., 2017).

Autoimmune-related diseases are associated with an increase in Th-17 lymphocytes (Dardalhon, Korn, Kuchroo, & Anderson, 2008; Korn, Bettelli, Oukka, & Kuchroo, 2009) that produce IL-17 and IL-22. Th-17 cells are boosting B cell responsivity (Mitsdoerffer et al., 2010) and are heavily regulated by IL-6 and TGF-β (Bettelli et al., 2006) produced during allergic reactions. IL-17 causes pain (Pinto et al., 2010) by sensitizing nociceptors (Segond von Banchet et al., 2013) while the pronociceptive effects of IL-22 are possibly indirectly mediated by neutrophils recruitment (Pinto et al., 2015). In addition, IL-22 promotes a Th-2 lymphocyte profile (Lou et al., 2017).

Finally, induction of the cyclooxygenase 2 (COX2) leads to the production of prostaglandins, notably PGE2, which causes pain (Chen, Tanner, & Levine, 1999; Minami et al., 1994) by sensitizing nociceptors (Chapman & Dickenson, 1992) and spinal nociceptive neurons (Baba, Kohno, Moore, & Woolf, 2001). PGE2 is a major immune signaling molecule that promotes Th2 T cells and reduces Th1 T cells (Harris, Padilla, Koumas, Ray, & Phipps, 2002). While PGE2 can be produced by many cell types, COX2 induction is extremely high in monocytes and macrophages.

Effects of Sleep Loss on Immune System and Pain in Baseline Conditions

Sleep deprivation is associated with an increase of the number of circulating leukocytes in healthy human subjects (Christoffersson et al., 2014; Faraut et al., 2012; Fondell et al., 2011; Ingram, Simpson, Malone, & Florida-James, 2015; Lasselin, Rehman, Akerstedt, Lekander, & Axelsson, 2015). Among leukocytes, circulating neutrophils and monocytes (blood-circulating precursors of macrophages) appear to be particularly sensitive to sleep loss with a rapid onset for their increase (Christoffersson et al., 2014; Faraut et al., 2012; M. R. Irwin et al., 2008; Lasselin et al., 2015), while T cells and B cells require a more substantial sleep loss or a chronic sleep restriction to show an increase (V. Aho et al., 2013; Fondell et al., 2011; Ingram et al., 2015; Lasselin et al., 2015; van Leeuwen et al., 2009). An acute sleep loss (4 hours sleep opportunity for 1 night) is sufficient to enhance the activity of the proinflammatory nuclear factor NFkB in monocytes, resulting in an increase of the production of cytokines such as TNFα, IL-1β, and IL-08 (Aho et al., 2013; Carroll et al., 2015; Dimitrov et al., 2015; M. R. Irwin et al., 2008; M. R. Irwin, Witarama, Caudill, Olmstead, & Breen, 2015) and C-reactive protein (V. Aho et al., 2013; van Leeuwen et al., 2009). Chronic sleep restriction (4 hours sleep opportunity for 5 nights) also causes a change in T and B cell functions, with an overall shift toward more Th2-type responses that lead to reduced levels of circulating IL-2 and increased levels of IL-6 and IL-17 (Axelsson et al., 2013; van Leeuwen et al., 2009). Finally, extended sleep deprivation further increases the production of IL-6 and also leads to elevated levels of PGE2 (Haack et al., 2007, 2009). Overall, these results indicate that sleep loss promotes the proinflammatory component of the innate immune response (monocytes/macrophages, neutrophils) and a shift toward allergic reactions and autoimmunity at the adaptive immune system level (Th2/Th17). All these changes are associated with an increase in pronociceptive signaling (IL-6, IL-1β, TNFα) and a reduction of antinociception (IL2), likely contributing to hyperalgesia.

In rats, a similar profile has been described after REM sleep deprivation with an increase in circulating leukocytes (Ibarra-Coronado et al., 2015) coupled with an increase in inflammatory responses (Yehuda, Sredni, Carasso, & Kenigsbuch-Sredni, 2009). In contrast, REM sleep deprivation in mice caused an overall decrease in blood leukocyte count (Guariniello, Vicari, Lee, De Oliveira, & Tufik, 2012; Lungato et al., 2012). This reduction in white blood cells is mostly accounted for by a decrease in circulating lymphocytes (Guariniello et al., 2012) caused by a production defect in the spleen (Lungato et al., 2012), while monocyte and neutrophil counts are actually higher in the blood (Guariniello et al., 2012). The increased number of monocytes and neutrophils is associated with elevated blood levels of IL-6 and IL-1β, and to some extend TNFα (Hu et al., 2003). In the remaining lymphocytes, REM sleep deprivation leads to a shift in T-cell subtypes in favor of Th-17 (Nunes et al., 2018). In the CNS, acute total sleep deprivation increases phagocytic activity of astrocytes and causes microglial activation (Bellesi et al., 2017), which can contribute to central sensitization and pain hypersensitivity (Latremoliere & Woolf, 2009). Despite a reduction in circulating lymphocytes, sleep loss in mice appears to promote a proinflammatory innate response coupled with a shift toward autoimmunity that leads to an overall enhancement of pronociceptive signaling.

Under baseline conditions, sleep loss changes the balance of the immune system, which leads to increased levels of proalgesic agents like TNFα, IL-1β, IL-6, or PGE2, which likely contribute to a heightened pain perception. Inhibition by the nonselective COX inhibitor ibuprofen does not reduce mechanical or heat hyperalgesia in mice (Alexandre et al., 2017), but it is possible that the elevated levels in prostaglandin observed after sleep loss specifically increase more systemic/spontaneous pain complaints reported by healthy subjects (Haack & Mullington, 2005; Schuh-Hofer et al., 2015) or migraine (Haack et al., 2009).

Sleep Loss on Immunity and Pain in Context of Active Infections

Sleep is an essential part of the physiological response to infection (Imeri & Opp, 2009) as it allows the organism to save energy and promotes the humoral immune response necessary to fight off infiltrating pathogens. Both in humans and mice, sleep loss increases the toll-like receptor 4 (TLR4)–mediated activation of monocytes/macrophages and neutrophils (Dassow, Lassner, Remke, & Preiss, 1998; Wisor, Clegern, & Schmidt, 2011). TLR4 is a major receptor of pathogen-associated ligands, so an increase in its activation is likely to lead to a faster innate immune response. Such increased responsivity together with the heightened baseline inflammatory profile was reported beneficial to fight infection in Drosophila (Kuo & Williams, 2014), but not in humans (Haack, Schuld, Kraus, & Pollmacher, 2001). One possible reason is that the increased influx of immune cells caused by sleep loss favors more immature cells (Christoffersson et al., 2014; Ingram et al., 2015), which are likely to mediate a less targeted and less efficient response at the site of injury. With sustained sleep restriction, the defect in innate responses aggravates, and this allows proliferation of opportunistic bacteria that can lead to death (Everson, 1993). Production and redeployment of antibody-producing B cells (Ingram et al., 2015; Zielinski et al., 2014) are strongly reduced by sleep loss, which delays the humoral response and hampers the immunization process (Lange, Perras, Fehm, & Born, 2003).

Overall, sleep loss disrupts the complex cross-talk between the innate and adaptive immune systems required to fight an infection efficiently. This leads to an abnormal initial immune response, with increased levels of proinflammatory factors which can promote pain sensitivity, but also a delayed and suboptimal humoral immune response that will increase the time needed to neutralize the pathogens. This delayed response is likely to maintain a “proinflammatory” state and pain hypersensitivity, and it significantly increases the risk of developing allergies or autoimmune reactions by promoting Th-2 and Th-17 responses over extended periods of time (Axelsson et al., 2013; Sá-Nunes et al., 2016; Zielinski et al., 2014).

Finally, sleep loss causes a decrease in circulating NK cell number and their cytotoxic function in both humans (Fondell et al., 2011; van Leeuwen et al., 2009) and mice (B. H. De Lorenzo, de Oliveira Marchioro, Greco, & Suchecki, 2015; B. H. P. De Lorenzo et al., 2018). NK cells are essential for the destruction of tumor or virus-infected cells, and a reduction of their function has been shown to exacerbate and prolong neuropathic pain symptoms (Davies et al., 2019). Sleep loss then could contribute to the development of chronic pain after peripheral nerve injury by preventing NK cells from clearing partially axotomized axons.

Overall, the deleterious effects of sleep loss on the immune system are strongly associated with a major shift toward the production of proalgesic factors. These effects have consequences under basal conditions by increasing the levels of sensitizing cytokines and prostaglandins circulating in the blood and, most likely, within tissues. Upon activation of the immune system by the detection of a pathogen, these levels are further augmented and maintained over extended periods of time, thus preventing the return to normal sensitivity and increasing the risk of developing abnormal pain states (Sutton & Opp, 2014; Vanini, 2016; P. K. Wang et al., 2015).

Within the Central Nervous System: Spinal Level

While a heightened sensitivity to detect noxious stimuli or an exaggerated response upon nociceptors activation is likely to lead to an overall increase in pain responses, sleep loss–induced changes within the CNS can also interfere with the experience and perception of pain by altering the descending pain pathways and the cognitive and affective/motivational processing of pain (Fig. 6).

Sleep loss can amplified nociceptive inputs at many levels within the CNS, starting at the dorsal horns of the spinal cord, where sensory processing is heavily processed (Latremoliere & Woolf, 2009). Under normal conditions, spinal nociceptive neurons are under a strong inhibitory influence by local segmental inhibition (GABA, Glycine), and excitatory nociceptive transmission is mostly carried out through postsynaptic glutamatergic AMPA receptors. After REM sleep deprivation, mechanical hyperalgesia can be partially prevented by intrathecal blockade of excitatory NMDAR or metabotropic mGluR (Wei, Zhao, Wang, & Pertovaara, 2007) and by promoting spinal segmental inhibition (Wei et al., 2010), suggesting a partial state of central sensitization. This overall gain in excitability is not associated with a major local neuroinflammation, however, as indicated by the absence of microglial activation in the spinal cord of sleep-deprived animals or the lack of effects of minocycline (an inhibitor of microglial activation) on REM sleep deprivation-induced hyperalgesia (Wei et al., 2010) and the limited effects of systemic ibuprofen (a nonspecific COX inhibitor) to reduce total sleep loss–induced hyperalgesia (Alexandre et al., 2017; Wodarski et al., 2015). After nerve injury, however, sleep deprivation aggravates mechanical allodynia and thermal hyperalgesia, and this is associated with an increase in microglial activation (Huang et al., 2014), suggesting that sleep deprivation could have additional effects on already weakened circuits.

Within the Central Nervous System: Descending Controls

In addition to local circuits, spinal nociceptive neurons can also be directly modulated by descending controls originating from several functionally interconnected brain structures, mostly located in the brainstem (Almeida, Størkson, Lima, Hole, & Tjølsen, 1999; Martins & Tavares, 2017; Millan, 2002; M. H. Ossipov, Dussor, & Porreca, 2010), although several direct corticospinal projections have recently been shown to play a major role in sensory processing (T. Chen et al., 2018; Liu et al., 2018). Descending pain pathways can facilitate (“descending excitatory controls”) or inhibit (“descending inhibitory controls”) pain transmission, and their activation can usually be triggered by activation of nociceptive neurons or by several brain structures involved in cognitive, emotional, or attentional processing.

The Periaqueductal Gray Matter and the Rostral Ventromedial Medulla

The periaqueductal gray matter (PAG) and the rostral ventromedial medulla (RVM) system represent a major supraspinal descending pathway that can critically influence the transmission of nociceptive signals (Basbaum & Fields, 1984; Millan, 2002) (Fig. 6). The PAG is a major source of descending opioid-mediated inhibition of nociceptive inputs (Fields, 2004; Ossipov, Morimura, & Porreca, 2014). In addition to spinal nociceptive projection neurons and cortical neurons/inputs (ACC), the PAG is also reciprocally connected with the amygdala, hypothalamus, thalamus, parabrachial nuclei, and RVM (Cameron, Khan, Westlund, & Willis, 1995; Fields, Basbaum, & Heinricher, 1999; Krout, Jansen, & Loewy, 1998). RVM neurons can either facilitate or inhibit behavioral pain responses based on the subtype of neuronal subpopulations recruited (Ossipov et al., 2014). Typically, “ON cells” facilitate nociceptive neurotransmission and “OFF cells” inhibit it, and the two populations exhibit reciprocal patterns of discharge (Fields et al., 1999). Opiates, including morphine, produce their analgesia action mostly through the PAG/RVM system by inhibiting “ON cells” and activating “OFF cells,” and this can be replicated by direct administration of morphine (Lewis & Gebhart, 1977) or electric stimulation of the PAG (Hosobuchi, Adams, & Linchitz, 1977).

Both total and REM sleep deprivation decrease the analgesic action of systemic morphine in both humans and rodents (Alexandre et al., 2017; Nascimento et al., 2007; Ukponmwan et al., 1984), and experiments on animal models have shown a key role of the PAG in this phenomenon. Micro-injection of morphine specifically into the ventral PAG of REM sleep-deprived rats caused a significantly blunted analgesic efficacy for mechanical pain behaviors compared to well-rested animals (Tomim et al., 2016). A similar reduction of PAG-mediated analgesia can be produced by local administrating bicuculline, a selective GABAA receptor agonist to inhibit “ON cells” of the RVM. While bicuculline increases mechanical paw withdrawal thresholds (analgesia) in all conditions, a much higher dose is required after REM sleep deprivation (Tomim et al., 2016) (indicating reduced analgesia), suggesting REM sleep deprivation causes an hyperexcitability of RVM “ON cells” that counteracts the analgesia normally caused by their inhibition. Finally, excitotoxic lesions of the ventral PAG that reduce the total number of neurons by ~20% are sufficient to prevent mechanical hyperalgesia induced by 12 days of chronic sleep restriction, without altering baseline pain responses (Sardi, Lazzarim, et al., 2018). Altogether these data show that sleep deprivation reduces PAG-RVM-mediated descending inhibition of spinal nociceptive transmission, and this participates in the development of sleep loss–induced hyperalgesia and contributes to the loss of efficacy of opiates that rely on the PAG-RVM system to produce analgesia.

In addition to the reduction of descending inhibitory controls activated by endorphins and opiates, REM sleep deprivation increases the excitatory cholecystokininergic descending pathways that originate from the RVM. Microinjection of a cholecystokinin receptor 2 (CCK2) agonist into the RVM causes mechanical pain hypersensitivity in controls, but not sleep-deprived animals, while microinjection of an antagonist or an excitotoxic lesion of the dorsolateral funiculus (DLF) of the spinal cord reduces the development of sleep loss–induced hyperalgesia (Sardi, Lazzarim, et al., 2018) (Fig. 6).

Another important nucleus in the RVM that massively projects into the dorsal horns of the spinal cord is the raphe magnus (RM; Kwiat & Basbaum, 1992). While lesions of the descending tracks originating from RM neurons increase pain responses, indicating a pain inhibitory role under normal conditions (A. I. Basbaum & Fields, 1978), this nucleus can actually promote either inhibition or facilitation of the nociceptive spinal transmission depending on the subsets of neurons activated and the nature of the neurotransmitters they produce. RM neurons that produce and release GABA, glycine, or neuropeptides (e.g., enkephalin) in the spinal cord promote analgesia, while those producing serotonin can again exert both pro and anti-nociceptive actions, depending on which receptors are activated (among more than 10 subtypes expressed in the spinal cord) and by which neurons (primary afferent fibers, projecting neurons, excitatory or inhibitory interneurons) (Hamon & Bourgoin, 1999; Millan, 2002). After REM sleep deprivation, the complex effects of modulating the serotonin receptors 5-HT1A and 5-HT2C at the spinal cord level on pain are unchanged, suggesting that the serotoninergic descending controls are not heavily affected by sleep loss in rats (Wei, Ma, Wang, & Pertovaara, 2008). Finally, in addition to the PAG, the RVM also receives inputs from the thalamus, the parabrachial region, and the noradrenergic locus coeruleus, which are themselves involved in the generation and modulation of sleep-wake patterns.

Diffuse Noxious Inhibitory Controls

Diffuse noxious inhibitory controls (DNICs) constitute a descending control system mediating the inhibition of one pain sensation by another noxious stimulus applied to a distant anatomic site innervated by a different dermatome (Villanueva & Le Bars, 1995) (“counterirritation”). DNICs are triggered by intense noxious stimuli and activate neurons located in the subnucleus reticularis dorsalis (Le Bars, 2002; Villanueva & Le Bars, 1995) (medullary reticular nucleus in mice) (Fig. 6). These neurons project back into the spinal cord, where they are thought to promote the most relevant (and intense) pain signal (Amorim et al., 2015; Martins & Tavares, 2017). In addition, DNICs activate a strong analgesia of the remaining nociceptive neurons, notably through β-adrenergic signaling (Bannister, Patel, Goncalves, Townson, & Dickenson, 2015; Lockwood, Bannister, & Dickenson, 2019), while activation (tonic or phasic) of the excitatory 5-HT3 receptor blocks the analgesic effects of DNICs (Bannister et al., 2015). DNICs likely involve the activation of several loops within the medulla and could modulate nociceptive signaling at several levels in the brain (Ossipov et al., 2014). Conditioned pain modulation (CPM) is the human psychophysical equivalent of DNICs (Yarnitsky, 2010; Yarnitsky et al., 2015). It is typically tested by the “RIII” nociceptive reflex, which is elicited by an electric stimulation of the sural nerve at the ankle level while a tonic noxious conditioning stimulus is applied onto a different dermatome (usually one hand immersed in a cold [5°C] water bath). DNICs assess the responses to a phasic noxious test stimulus (electric stimulation) before and during the application of the tonic noxious conditioning stimulus (the cold-water bath that activates endogenous descending inhibitory pathways). Both the RIII reflex and the associated painful sensation are depressed with intense conditioning stimuli independent of modality (cold, heat, pressure), indicating an inhibition that occurs spinally (at least in part).

Sleep disturbances are associated with a loss of DNICs, and this effect seems more prominent in females. In healthy women, three nights of experimentally fragmented sleep associated with partial sleep loss result in a loss of DNICs and the development of spontaneous pain symptoms (M. T. Smith et al., 2007), while restricted, but consolidated sleep (i.e., one night TSD) does not (Eichhorn et al., 2018; Matre, Knardahl, & Nilsen, 2017; M. T. Smith et al., 2007). In line with this, night shift work, which reduces without fragmenting sleep, does not affect DNICs but increases pain sensitivity (Matre et al., 2017). Sleep architecture during the forced awakening protocol is associated with a specific loss of NREM sleep N3 stage (slow-wave sleep) and a subsequent increase in NREM sleep N1 stage, something not observed with sleep restriction (that maintains the overall sleep architecture; Alexandre et al., 2017), and this could point to a key mechanism whereby selective loss of N3 NREM sleep leads to a loss of DNICs, and possibly other endogenous inhibitory pain modulation mechanisms. Interestingly, changes in DNICs parallel changes in clinical pain and pain-associated symptoms, and a better sleep continuity in patients with chronic temporomandibular joint disorder is associated with better-functioning DNICs (Edwards et al., 2009; Smith et al., 2009).

Within the Central Nervous System: Reward/Limbic System

Another critical neurological link involved in the relationship between sleep and pain is the reward system and dopaminergic neurotransmission. Dopamine (DA) is essential for the regulation of motivated behaviors and is a key neurotransmitter of the reward circuitry, but recent work has shown its importance on the sleep-wake cycle as well (Oishi & Lazarus, 2017). This role is perhaps not entirely surprising as motivated behaviors typically require high arousal levels (Eban-Rothschild, Rothschild, Giardino, Jones, & de Lecea, 2016) and most wake-promoting drugs (modafinil, amphetamine) actually enhance dopamine tone (Boutrel & Koob, 2004). In humans, one night of sleep deprivation decreases D2/D3 receptor availability in the striatum and thalamus (Volkow et al., 2008), likely through downregulation of these receptors in sleep-deprived states (Volkow et al., 2012).

Several lines of evidence have indicated a major role of the limbic system in sleep loss–induced hyperalgesia both in rodents and humans. Numerous studies have shown that pain sensitivity and the spinal response to noxious stimuli are augmented by negative affective stimuli and inhibited by positive affective stimuli (Rhudy, 2016). In 2014, Del Ventura et al. (2013) revealed for the first time that insomnia symptoms were associated with attenuated positive affective pain inhibition, but not augmented negative affective pain facilitation (DelVentura, Terry, Bartley, & Rhudy, 2013). Finan et al. (2017) followed that cross-sectional study with a within-subject sleep disruption experiment in healthy, good sleepers (Finan et al., 2017). After one night of sleep disruption, and again after one night of normal sleep, subjects were exposed to an affective pain modulation task in which positive, negative, and neutral emotionally evocative images were paired with noxious thermal stimuli. Results confirmed and extended Del Ventura et al.’s initial cross-sectional data, showing that a single night of sleep disruption attenuated positive affective pain inhibition without altering negative affective pain facilitation. Furthermore, the Finan et al. (2017) results have been confirmed and extended using positive emotional (versus neutral) music following experimental sleep disruption in a different cohort of healthy participants (Seminowicz et al., 2019). Together, these findings suggest that sleep disturbance may threaten the protective effect of positive affect on pain.

The nucleus accumbens (NAc) is both functionally connected to brain regions linked with affective function (Salgado & Kaplitt, 2015) and directly involved in the appraisal of salient rewarding and aversive stimuli (Al-Hasani et al., 2015; Cooper & Knutson, 2008; Knutson, Adams, Fong, & Hommer, 2001; Roitman, Wheeler, & Carelli, 2005). Experimental sleep deprivation studies show that, following one night of total sleep deprivation, NAc activation increases in response to the presentation of rewarding stimuli (Gujar, Yoo, Hu, & Walker, 2011; Mullin et al., 2013; Venkatraman, Chuah, Huettel, & Chee, 2007; Venkatraman, Huettel, Chuah, Payne, & Chee, 2011). Under rested conditions, NAc activation increases at the onset of noxious thermal stimuli (Baliki & Apkarian, 2015; Seminowicz et al., 2019). Until recently, however, no study had investigated the effects of sleep deprivation on pain-related NAc function. Two such studies have recently been published. Krause et al. (2019) found that one night of total sleep deprivation reduced bilateral NAc activation during a noxious thermal stimulus in healthy subjects (Krause, Prather, Wager, Lindquist, & Walker, 2019). Similarly, Seminowicz et al. (2019) found that that NAc function during the onset of noxious thermal stimuli was bilaterally reduced following one night of sleep disruption via forced nocturnal awakenings (Seminowicz et al., 2019). Interestingly, during the tonic plateau of the noxious thermal stimulus, NAc activation was greater following sleep disruption relative to normal sleep (Seminowicz et al., 2019). These findings could indicate that sleep deprivation results in a delayed evaluation of threat, such that the salience of the initial stimulus is reduced, but the subsequent counterregulatory response is enhanced in compensation. Additionally, increased NAc activation during the plateau of a painful stimulus may reflect a deficit in descending pain modulation engendered by sleep disruption.

The nucleus accumbens is also a major contributor in setting up the pronociceptive effect of sleep loss in rats. Excitotoxic lesion by NMDA administration either into the core or the shell of the NAc prevents the mechanical hypersensitivity induced by REMSD and chronic sleep restriction (Sardi, Lazzarim, et al., 2018; Sardi, Tobaldini, et al., 2018). Local activation of adenosine A2A receptors by infusion into the NAc prevented the full recovery of the hyperalgesia induced by 24 hours of REMSD (~8 hours NREM sleep lost). In contrast, blocking adenosine A2A or activating D2 receptors at the NAc core blocked the development of REMSD-induced mechanical hyperalgesia, but also increased the general locomotor activity of the animals. Taken together, these results suggest that the NAc mediates the pronociceptive effect of sleep loss, by locally increasing the activity of adenosine A2A receptors transmission and decreasing the activity of dopamine D2 receptors. The NAc mediates the pronociceptive effect of REMSD because it was prevented by NAc excitotoxic lesion and reverted by NAc acute blockade. The pronociceptive effect of REMSD depends on increased activity at adenosine A2A receptors and decreased activity at dopamine D2 receptors located in the NAc because local administration of an A2A antagonist or of a D2 agonist blocked such an effect. In support of this, Alexandre et al. (2017) showed that both caffeine and modafinil can restore normal pain sensitivity in sleep-deprived mice, without causing any analgesia in well-rested mice. The action of caffeine and modafinil could converge to the NAc for their promotion of alertness, which can block sleep loss–induced pain hypersensitivity.

Effects of Sleep on Cognitive Processing of Pain

Lack of sleep impairs dramatically numerous cognitive processes, including attentional control (Killgore, 2010). Deficits in vigilant attention appear to underlie many sleep loss–induced cognitive impairments (Lim & Dinges, 2008) by prejudicing the effective allocation of attention to relevant stimuli (Gunter, van der Zande, Wiethoff, Mulder, & Mulder, 1987) and ignoring irrelevant or misleading information (McCarthy & Waters, 1997). On the other hand, attentional focus, the formation of expectations, and experience reappraisal can influence pain perception and thus bias nociceptive processing (Wiech, Ploner, & Tracey, 2008).

Variations in attentional focus strongly affect pain perception: Noxious stimuli are perceived as less intense when subjects are distracted and more painful when they are focused on the noxious stimuli (Legrain, Guerit, Bruyer, & Plaghki, 2002; Miron, Duncan, & Bushnell, 1989; Petrovic, Petersson, Ghatan, Stone-Elander, & Ingvar, 2000). Lower self-reported sleep durations are associated with diminished distraction analgesia (C. M. Campbell et al., 2011), and acute experimental sleep restriction not only increased subjective pain perception (ratings) but also reduced the ability of attention to modulate pain, while leaving sensory discrimination intact (Tiede et al., 2010). These findings indicate that insufficient sleep weakens the ability to attend to and disengage oneself from painful stimuli, so that the net outcome is an exaggerated pain sensation.

Pain perception is also strongly shaped by past experiences and expectations: When pain is expected, it is often experienced with a greater intensity, and vice-versa. The placebo response is a familiar and powerful illustration of the critical influence that expectations have on pain perception and treatment outcome. Placebo hypoalgesia is the result of combining prior expectations or predictions of pain (relief) with sensory signals (Okusogu & Colloca, 2019). Recently it has been reported that cognitive processes underlying the placebo response, such as learning and the formation/consolidation of expectations, are sleep dependent and therefore sensitive to sleep loss (Chouchou et al., 2015; Laverdure-Dupont, Rainville, Montplaisir, & Lavigne, 2009; Laverdure-Dupont, Rainville, Renancio, Montplaisir, & Lavigne, 2018). REM sleep appears to be involved in the reprocessing of relief expectations generated prior to sleep (Chouchou et al., 2015), suggesting that placebo mechanisms may involve sleep-related processing.

Conclusion

Despite significant differences in sleep-wake patterns between humans and rodents and a great heterogeneity in protocols used to disturb sleep, the effects of sleep disturbance on pain sensitivity are remarkably conserved across species.

The major parameter responsible for sleep deprivation–induced pain hypersensitivity does not appear to be the loss of one specific sleep state (i.e., REM sleep, N3 NREM sleep) or the continuity of sleep (i.e., fragmented without total sleep loss) but the amount of total sleep lost. Several protocols can be used to decrease sleep: delaying sleep onset, interrupting sleep by forced awakenings, or waking up earlier than normal. The proalgesic effect of sleep loss occurs relatively early (loss of 40–50% of total sleep compared to the baseline amount) and is dose dependent. In addition, when exposed to mild but repeated sleep restriction, sleep loss–induced hyperalgesia is cumulative despite a normal sleep homeostasis. With the vast majority of the population considered somewhat chronically sleep deprived (missing a couple of hours per night) and relying on “days off” to recover (weekend), this build-up of sleep debt and heightened pain sensitivity might represent a major public health risk. The development of nociceptive hypersensitivity differs among different modalities (thermal, mechanical, chemical, spontaneous), suggesting that specific mechanisms are involved.

Sleep loss–induced pain hyperalgesia is not fully prevented by classic analgesics (NSAIDS, morphine), whose efficacy is even reduced under conditions of insufficient sleep. While problematic for healthy individuals, the situation is even more concerning for chronic pain patients, as sleep loss exacerbates existing pain hypersensitivity, further blunts the efficacy of their treatment, and delays recovery.

Sleep deprivation does not seem to affect sensory processing of innocuous stimuli, indicating that sleep loss–induced pain hypersensitivity is not caused by a general state of hyperresponsiveness, but rather by selective impairments within the pain pathways.

Sleep loss causes a shift in the immune system towards more proinflammatory states, associated with increased peripheral sensitization of nociceptors. Acute sleep loss will preferentially affect the reactivity of neutrophils and macrophages, while chronic sleep restriction increases lymphocyte number and reactivity, which can further dysregulate normal immune responses and extend the duration of peripheral sensitization. NK cells are reduced by sleep loss, which could impair normal recovery after injury and lead to maladaptive chronic pain.

Sleep deficiency affects numerous physiological systems, which in turn can alter one or more aspects of pain processing (sensory-discriminative, cognitive, emotional), leading to a wide variety of outcomes. A lack of sleep also alters the functional state of the first nociceptive synapse at the spinal cord level by increasing excitatory transmission while reducing inhibitory processes. This reduced inhibition of spinal nociceptive neurons is due to a loss of both local inhibitory processes and descending inhibitory controls that originate from the brainstem. These controls are important to set baseline pain thresholds but also contribute to pain tolerance, both of which are reduced after sleep loss, especially in females. While both males and females experience hyperalgesia after sleep loss, recent studies revealed gender-specific differences in the underlying mechanisms. Finally, recent lines of investigations have highlighted a critical role of the mesolimbic system in mediating the pronociceptive effect of insufficient sleep, by altering the processing of noxious (aversive) stimuli.

Overall, because sleep itself lessens the hyperalgesic effects of sleep deprivation in animal models and extending sleep in healthy volunteers after sleep restriction reduces pain hypersensitivity, sleep management in pain patients with sleep disturbances might represent an effective strategy to improve pain symptoms and preserve the maximum efficacy of analgesics.

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