Mackenzie C Gamble1,2, Byron Chuan3, Teresa Gallego-Martin3, Micah A Shelton4, Stephanie Puig1, Christopher P O'Donnell3, Ryan W Logan5,6,7. 1. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA. 2. Molecular and Translational Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA. 3. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. 4. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. 5. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA. rwlogan@bu.edu. 6. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. rwlogan@bu.edu. 7. Center for Systems Neuroscience, Boston University, Boston, MA, 02118, USA. rwlogan@bu.edu.
Abstract
RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Darius D Becker-Krail; Puja K Parekh; Kyle D Ketchesin; Shintaro Yamaguchi; Jun Yoshino; Mariah A Hildebrand; Brandan Dunham; Madhavi K Ganapathiraju; Ryan W Logan; Colleen A McClung Journal: Eur J Neurosci Date: 2022-01-20 Impact factor: 3.698
Authors: Lauren M DePoy; Darius D Becker-Krail; Wei Zong; Kaitlyn Petersen; Neha M Shah; Jessica H Brandon; Alyssa M Miguelino; George C Tseng; Ryan W Logan; Colleen A McClung Journal: J Neurosci Date: 2020-12-02 Impact factor: 6.167
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