Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA.
Molecular and Translational Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.
Psychopharmacology (Berl). 2022 Oct;239(10):3185-3200. doi: 10.1007/s00213-022-06200-x. Epub 2022 Aug 1.
Synthetic opioids like fentanyl are contributing to the rise in rates of opioid use disorder and drug overdose deaths. Sleep dysfunction and circadian rhythm disruption may worsen during opioid withdrawal and persist during abstinence. Severe and persistent sleep and circadian alterations are putative factors in opioid craving and relapse. However, very little is known about the impact of fentanyl on sleep architecture and sleep-wake cycles, particularly opioid withdrawal. Further, circadian rhythms regulate sleep-wake cycles, and the circadian transcription factor, neuronal PAS domain 2 (NPAS2) is involved in the modulation of sleep architecture and drug reward. Here, we investigate the role of NPAS2 in fentanyl-induced sleep alterations.
To determine the effect of fentanyl administration and withdrawal on sleep architecture, and the role of NPAS2 as a factor in fentanyl-induced sleep changes.
Electroencephalography (EEG) and electromyography (EMG) was used to measure non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS) at baseline and following acute and chronic fentanyl administration in wild-type and NPAS2-deficient male mice.
Acute and chronic administration of fentanyl led to increased wake and arousal in both wild-type and NPAS2-deficient mice, an effect that was more pronounced in NPAS2-deficient mice. Chronic fentanyl administration led to decreased NREMS, which persisted during withdrawal, progressively decreasing from day 1 to 4 of withdrawal. The impact of fentanyl on NREMS and arousal was more pronounced in NPAS2-deficient mice.
Chronic fentanyl disrupts NREMS, leading to a progressive loss of NREMS during subsequent days of withdrawal. Loss of NPAS2 exacerbates the impact of fentanyl on sleep and wake, revealing a potential role for the circadian transcription factor in opioid-induced sleep changes.
芬太尼等合成阿片类药物的使用导致阿片类药物使用障碍和药物过量死亡的发生率上升。在阿片类药物戒断期间和戒断期间，睡眠功能障碍和昼夜节律紊乱可能会恶化。严重和持续的睡眠和昼夜节律改变是阿片类药物渴求和复发的潜在因素。然而，人们对芬太尼对睡眠结构和睡眠-觉醒周期的影响知之甚少，特别是在阿片类药物戒断期间。此外，昼夜节律调节睡眠-觉醒周期，昼夜节律转录因子神经元 PAS 结构域 2（NPAS2）参与调节睡眠结构和药物奖励。在这里，我们研究了 NPAS2 在芬太尼引起的睡眠改变中的作用。
确定芬太尼给药和戒断对睡眠结构的影响，以及 NPAS2 作为芬太尼引起的睡眠变化的一个因素的作用。
在野生型和 NPAS2 缺陷型雄性小鼠中，使用脑电图（EEG）和肌电图（EMG）在基线以及急性和慢性芬太尼给药后测量非快速眼动睡眠（NREMS）和快速眼动睡眠（REMS）。
急性和慢性芬太尼给药导致野生型和 NPAS2 缺陷型小鼠的觉醒和唤醒增加，NPAS2 缺陷型小鼠的这种作用更为明显。慢性芬太尼给药导致 NREMS 减少，这种减少在戒断期间持续存在，从戒断的第 1 天到第 4 天逐渐减少。芬太尼对 NREMS 和唤醒的影响在 NPAS2 缺陷型小鼠中更为明显。
慢性芬太尼扰乱 NREMS，导致随后戒断期间 NREMS 的逐渐丧失。NPAS2 的缺失加剧了芬太尼对睡眠和觉醒的影响，揭示了昼夜节律转录因子在阿片类药物引起的睡眠变化中的潜在作用。
