Chronic sleep restriction increases pain sensitivity over time in a periaqueductal gray and nucleus accumbens dependent manner

Highlights

• Sleep restriction for 6 h daily induces a pronociceptive effect.

• The effect increases progressively from day 3 to day 12 remaining stable thereafter.

• Two consecutive days of free sleep were not enough to reverse the effect.

• Chronic sleep restriction increases pain sensitivity in a NAc and PAG dependent manner.

• c-Fos protein expression within the NAc and PAG correlates with the pronociceptive effect.

Abstract

Painful conditions and sleep disturbances are major public health problems worldwide and one directly affects the other. Sleep loss increases pain prevalence and severity; while pain disturbs sleep. However, the underlying mechanisms are largely unknown. Here we asked whether chronic sleep restriction for 6 h daily progressively increases pain sensitivity and if this increase is reversed after two days of free sleep. Also, whether the pronociceptive effect of chronic sleep restriction depends on the periaqueductal grey and on the nucleus accumbens, two key regions involved in the modulation of pain and sleep-wake cycle. We showed that sleep restriction induces a pronociceptive effect characterized by a significant decrease in the mechanical paw withdrawal threshold in rats. Such effect increases progressively from day 3 to day 12 remaining stable thereafter until day 26. Two consecutive days of free sleep were not enough to reverse the effect, not even to attenuate it. This pronociceptive effect depends on the periaqueductal grey and on the nucleus accumbens, since it was prevented by their excitotoxic lesion. Complementarily, chronic sleep restriction significantly increased c-Fos protein expression within the periaqueductal grey and the nucleus accumbens and this correlates with the intensity of the pronociceptive effect, suggesting that the greater the neural activity in this regions, the greater the effect. These findings may contribute not only to understand why painful conditions are more prevalent and severe among people who sleep poorly, but also to develop therapeutic strategies to prevent this, increasing the effectiveness of pain management in this population.

Introduction

Pain conditions and sleep disorders are major public health problems worldwide (Appleton et al., 2018; Murphy et al., 2017) and there is a clear bidirectional relationship between them. There is no doubt that pain impairs sleep (Artner et al., 2013; Karaman et al., 2014) and different types of sleep impairment increase pain sensitivity (Okifuji and Hare, 2011). However, the underlying mechanisms are largely unknown.

The reason why sleep disorders are great predictors of pain development (Mork and Nilsen, 2012; Okifuji and Hare, 2011) may rely on the ability of sleep loss to disrupt endogenous pain modulation, as suggested by clinical findings (Paul-Savoie et al., 2012; Tiede et al., 2010). In fact, several brain regions that play a key role in pain modulation, such as the ventrolateral periaqueductal gray (vlPAG) (Fields, 2004), and the Nucleus Accumbens (NAc), (Gear et al., 1999), also contribute to control sleep-wake cycle (Lu et al., 2006; Oishi et al., 2017; Weber et al., 2018). Since most sleep disorders are characterized by impairment mainly in rapid eye movement (REM) sleep (Brown et al., 2012; Naiman, 2017), we have performed REM sleep deprivation (REM-SD) in rats to provide a mechanistic basis for these clinical observations. According to our previous data, REM-SD increases nociceptive responses by disrupting the PAG-RVM (periaqueductal gray – rostral ventral medulla) descending pain modulation system (Tomim et al., 2016) as well as by increasing NAc adenosinergic activity and by decreasing NAc dopaminergic activity (Sardi et al., 2018).

However, insomnia (Calhoun et al., 2014) and restriction of sleep time due to occupational or recreational reasons have become increasingly frequent in the modern society (Owens et al., 2014). In order to mimic this decrease in sleep duration in laboratory animals, some types of gentle stimulation have been used to keep them awake for long periods of time. Like selective REM-SD (Damasceno et al., 2009; Nascimento et al., 2007; Sardi et al., 2018; Tomim et al., 2016; Wei et al., 2013), sleep restriction (SR) has been associated with increased pain sensitivity in both humans (Okifuji and Hare, 2011; Tiede et al., 2010) and animals (Alexandre et al., 2017). However, the underlying mechanisms are largely unknown and many unanswered questions remain. For example: Does the pronociceptive effect of sleep restriction increase over time? If yes, when does it reach the maximum intensity? Are two days of normal sleep (mimicking free sleep on weekends) enough to normalize pain sensitivity? Is the pronociceptive effect of chronic sleep restriction also dependent on the PAG and on the NAc? If yes, the neuronal activity within these regions increases with chronic sleep restriction? This study aimed to answer these questions.