PDF(Pubmed)
Abstract：
Fentanyl has become the leading driver of opioid overdoses in the United States. Cessation of opioid use represents a challenge as the experience of withdrawal drives subsequent relapse. One of the most prominent withdrawal symptoms that can contribute to opioid craving and vulnerability to relapse is sleep disruption. The endocannabinoid agonist, 2-Arachidonoylglycerol (2-AG), may promote sleep and reduce withdrawal severity; however, the effects of 2-AG on sleep disruption during opioid withdrawal have yet to be assessed. Here, we investigated the effects of 2-AG administration on sleep-wake behavior and diurnal activity in mice during withdrawal from fentanyl. Sleep-wake activity measured via actigraphy was continuously recorded before and after chronic fentanyl administration in both male and female C57BL/6J mice. Immediately following cessation of fentanyl administration, 2-AG was administered intraperitoneally to investigate the impact of endocannabinoid agonism on opioid-induced sleep disruption. We found that female mice maintained higher activity levels in response to chronic fentanyl than male mice. Furthermore, fentanyl administration increased wake and decreased sleep during the light period and inversely increased sleep and decreased wake in the dark period in both sexes. 2-AG treatment increased arousal and decreased sleep in both sexes during first 24-h of withdrawal. On withdrawal day 2, only females showed increased wakefulness with no changes in males, but by withdrawal day 3 male mice displayed decreased rapid-eye movement sleep during the dark period with no changes in female mice. Overall, repeated administration of fentanyl altered sleep and diurnal activity and administration of the endocannabinoid agonist, 2-AG, had sex-specific effects on fentanyl-induced sleep and diurnal changes.
摘要：
芬太尼已成为美国阿片类药物过量的主要驱动因素。停止阿片类药物的使用是一个挑战，因为戒断的经历会导致随后的复发。可能导致阿片类药物渴望和易复发的最突出的戒断症状之一是睡眠中断。内源性大麻素激动剂，2-花生四酰基甘油（2-AG），可以促进睡眠和减少戒断的严重程度;然而，2-AG对阿片类药物戒断期间睡眠中断的影响尚待评估.这里,我们研究了2-AG给药对芬太尼戒断期间小鼠睡眠-觉醒行为和昼夜活动的影响.在雄性和雌性C57BL/6J小鼠中，在慢性芬太尼给药之前和之后，连续记录通过肌动描记术测量的睡眠-觉醒活动。立即停止芬太尼给药后，腹膜内施用2-AG以研究内源性大麻素激动对阿片样物质诱导的睡眠中断的影响。我们发现，雌性小鼠对慢性芬太尼的反应比雄性小鼠保持更高的活性水平。此外，在两种性别中，芬太尼给药在光照期增加了觉醒，减少了睡眠，在黑暗期增加了睡眠，减少了觉醒。在戒断的最初24小时内，2-AG治疗会增加两性的唤醒并减少睡眠。在戒断第2天，只有女性表现出觉醒增加，男性没有变化，但是到第3天，雄性小鼠在黑暗时期显示出减少的快速眼动睡眠，雌性小鼠没有变化。总的来说,反复服用芬太尼会改变睡眠和昼夜活动以及服用内源性大麻素激动剂，2-AG,对芬太尼诱导的睡眠和昼夜变化有性别特异性影响。
