Abstract
Dexmedetomidine, a highly selective α2-adrenergic agonist, is widely used in clinical anesthesia and ICU sedation. Recent studies have found that dexmedetomidine-induced sedation resembles the recovery sleep that follows sleep deprivation, but whether orally delivered dexmedetomidine can be a candidate for the treatment of insomnia remains unclear. In this study, we estimated the sedative effects of orally delivered dexmedetomidine by spontaneous locomotor activity (LMA), and then evaluated the hypnotic effects of dexmedetomidine on sleep–wake profiles during the dark and light phase using electroencephalography/electromyogram (EEG/EMG), respectively. Using c-Fos staining, we explored the effects of dexmedetomidine on the cerebral cortex and the sub-cortical sleep–wake regulation systems. The results showed that orally delivered dexmedetomidine at 2 h into the dark cycle reduced LMA and wakefulness in a dose-dependent manner, which was consistent with the increase in non-rapid eye movement sleep (NREM sleep). However, dexmedetomidine also induced a rebound in LMA, wake and rapid eye movement sleep (REM sleep) in the later stage. In addition, orally delivered dexmedetomidine 100 μg/kg at 2 h into the light cycle shortened the latency to NREM sleep and increased the duration of NREM sleep for 6 h, while decreased REM sleep for 6 h. Sleep architecture analysis showed that dexmedetomidine stabilized the sleep structure during the light phase by decreasing sleep–wake transition and increasing long-term NREM sleep (durations of 1024–2024 s and >2024 s) while reducing short-term wakefulness (duration of 4–16 s). Unlike the classic hypnotic diazepam, dexmedetomidine also increased the delta power in the EEG spectra of NREM sleep, especially at the frequency of 1.75–3.25 Hz, while ranges of 0.5–1.0 Hz were decreased. Immunohistochemical analysis showed that orally delivered dexmedetomidine 100 μg/kg at 2 h into the dark cycle decreased c-Fos expression in the cerebral cortex and sub-cortical arousal systems, while it increased c-Fos expression in the neurons of the ventrolateral preoptic nucleus. These results indicate that orally delivered dexmedetomidine can induce sedative and hypnotic effects by exciting the sleep-promoting nucleus and inhibiting the wake-promoting areas.
Highlights
Sleep exists in the overwhelming majority of organisms, from humans to worms (Allada and Siegel, 2008)
When dexmedetomidine was increased to 50 μg/kg, locomotor activity (LMA) was reduced by 87% (P < 0.01) and 84% (P < 0.01) compared with control group during the second and third hour after administration (Figure 1B)
Analysis of the number of c-Fos immunoreactive nuclei showed that dexmedetomidine 100 μg/kg decreased the number in the motor cortex by 71% (P < 0.01; Figure 6C). These results indicate that dexmedetomidine inhibits the activity of the cerebral cortex, which is consistent with the observations of decreased LMA and increased NREN sleep induced by dexmedetomidine during the dark phase
Summary
Sleep exists in the overwhelming majority of organisms, from humans to worms (Allada and Siegel, 2008). Insomnia is a common sleep disorder, defined as a complaint of prolonged sleep latency, difficulties in maintaining sleep, and subsequent impairments in daytime functioning (Riemann et al, 2010). The pharmacologic approach primarily includes benzodiazepines and non-benzodiazepines These classic hypnotics all act on gamma-aminobutyric acid type A receptors, mediating inhibition of the CNS and improving sleep related problems (Richey and Krystal, 2011; Uygun et al, 2016). These drugs reduce the depth of NREM sleep, and do not mimic physiological sleep (Akeju and Brown, 2017). Other hypnotics, such as antihistamines, antipsychotics, and melatonin, are not recommended for insomnia treatment due to side-effects according to the European Guideline for the diagnosis and treatment of insomnia (Riemann et al, 2017)
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