Intermittent REM sleep deprivation attenuates the development of morphine tolerance and dependence in male rats

Opioid agonists are used in clinic for pain management, however this application is challenged by development of tolerance and dependence following prolonged exposure. Various approaches have been suggested to address this concern, however, there is still no consensus among the researchers. Neural processing of sleep and nociception are co-regulated through shared brain regions having bidirectional interplays. Thus, we aimed to investigate whether application of REM sleep deprivation (REM-SD) could affect morphine analgesic tolerance and dependence. To this end, adult male rats underwent sleep deprivation during light and dark phases (LSD and DSD, respectively) using the inverted flower pot method and then tolerance and dependence was induced by repeated injection of morphine for 7 days (10 mg/kg, daily, i.p.). Results indicated that REM-SD delays the development of tolerance to morphine during both phases; however this effect was more potent following LSD. Moreover, LSD decreased the baseline thermal threshold and total withdrawal score. One possible hypothesis for our observations is REM-SD-induced attenuation of orexin system which is still controversial among the researchers. Other stronger possibilities might be down-regulation of opioid receptors in response to sleep loss experience. Finally, it seems that modification of sleep periods may assist to decrease the severity of opioid tolerance and dependence.