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.
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References
Ahmadi-Soleimani SM, Azizi H, Abbasi-Mazar A (2021) Intermittent REM sleep deprivation attenuates the development of morphine tolerance and dependence in male rats. Neurosci Lett 748:135735. https://doi.org/10.1016/j.neulet.2021.135735
Baidoo N, Wolter M, Leri F (2020) Opioid withdrawal and memory consolidation. Neurosci Biobehav Rev 114:16–24. https://doi.org/10.1016/j.neubiorev.2020.03.029
Barbosa-Leiker C, Campbell ANC, McHugh RK et al (2021) Opioid use disorder in women and the implications for treatment. PRCP 3:3–11. https://doi.org/10.1176/appi.prcp.20190051
Becker-Krail DD, Parekh PK, Ketchesin KD, Yamaguchi S, Yoshin J, Hildebrand MA, Dunham B, Ganapathiraju MK, Logan RW, McClung CA (2022) Circadian transcription factor NPAS2 and NAD+ -dependent deacetylase SIRT1 interact in the mouse nucleus accumbens and regulate reward. Eur J Neurosci 55:675–693. https://doi.org/10.1111/ejn.15464
Benington JH, Kodali SK, Heller HC (1994) Scoring transitions to REM sleep in rats based on the EEG phenomena of pre-REM sleep: an improved analysis of sleep structure. Sleep 17:28–36. https://doi.org/10.1093/sleep/17.1.28
Beswick T, Best D, Bearn J, Gossop M, Rees S, Strang J (2003) The effectiveness of combined naloxone/lofexidine in opiate detoxification: results from a double-blind randomized and placebo-controlled trial. Am J Addict 12:295–305. https://doi.org/10.1111/j.1521-0391.2003.tb00544.x
Ciccarone D (2019) The triple wave epidemic: supply and demand drivers of the US opioid overdose crisis. Int J Drug Policy 71:183–188. https://doi.org/10.1016/j.drugpo.2019.01.010
Comer SD, Cahill CM (2019) Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment. Neurosci Biobehav Rev 106:49–57. https://doi.org/10.1016/j.neubiorev.2018.12.005
De Andrés I, Caballero A (1989) Chronic morphine administration in cats: effects on sleep and EEG. Pharmacol Biochem Behav 32:519–526. https://doi.org/10.1016/0091-3057(89)90191-3
DePoy LM, Becker-Krail DD, Zong W, Petersen K, Shah NM, Brandon JH, Miguelino AM, Tseng GC, Logan RW, McClung CA (2021) J Neurosci 41:1046–1058. https://doi.org/10.1523/JNEUROSCI.1830-20.2020
Dudley CA, Erbel-Sieler C, Estill SJ et al (2003) Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science 301:379–83. https://doi.org/10.1126/science.1082795
Eacret D, Veasey SC, Blendy JA (2020) Bidirectional relationship between opioids and disrupted sleep: putative mechanisms. Mol Pharmacol 98:445–453. https://doi.org/10.1124/mol.119.119107
Eacret D, Lemchi C, Caulfield JI et al (2022) Chronic sleep deprivation blocks voluntary morphine consumption but not conditioned place preference in mice. Front Neurosci 16:836693. https://doi.org/10.3389/fnins.2022.836693
Fathi HR, Yoonessi A, Khatibi A et al (2020) Crosstalk between sleep disturbance and opioid use disorder: a narrative review. Addict Health 12:140–158. https://doi.org/10.22122/ahj.v12i2.249
Franken P, Dijk D-J (2009) Circadian clock genes and sleep homeostasis. Eur J Neurosci 29:1820–1829. https://doi.org/10.1111/j.1460-9568.2009.06723.x
Franken P, Dudley CA, Estill SJ et al (2006) NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: genotype and sex interactions. Proc Natl Acad Sci U S A 103:7118–7123. https://doi.org/10.1073/pnas.0602006103
Garcia JA, Zhang D, Estill SJ et al (2000) Impaired cued and contextual memory in NPAS2-deficient mice. Science 288:2226–2230. https://doi.org/10.1126/science.288.5474.2226
Gladden RM, Martinez P, Seth P (2016) Fentanyl Law Enforcement Submissions and Increases in Synthetic Opioid–Involved Overdose Deaths — 27 States, 2013–2014. MMWR Morb Mortal Wkly Rep 65. https://doi.org/10.15585/mmwr.mm6533a2
Hartwell EE, Pfeifer JG, McCauley JL, Moran-Santa Maria M, Back SE (2014) Sleep disturbances and pain among individuals with prescription opioid dependence. Addict Behav 39:1537–1542. https://doi.org/10.1016/j.addbeh.2014.05.025
Huhn AS, Berry MS, Dunn KE (2019) Review: sex-based differences in treatment outcomes for persons with opioid use disorder. Am J Addict 28:246–261. https://doi.org/10.1111/ajad.12921
Kay DC (1975) Human sleep during chronic morphine intoxication. Psychopharmacologia 44:117–124. https://doi.org/10.1007/BF00420997
Kay DC, Eisenstein RB, Jasinski DR (1969) Morphine effects on human REM state, waking state and NREM sleep. Psychopharmacologia 14:404–416. https://doi.org/10.1007/BF00403581
Kelly E, Sutcliffe K, Cavallo D, et al (2021) The anomalous pharmacology of fentanyl. British J Pharmacol 1:.https://doi.org/10.1111/bph.15573
Khazan N, Colasanti B (1972) Protracted rebound in rapid movement sleep time and electroencephalogram voltage output in morphine-dependent rats upon withdrawal. J Pharmacol Exp Ther 183:23–30
Lewis SA, Oswald I, Evans JI et al (1970) Heroin and human sleep. Electroencephalogr Clin Neurophysiol 28:374–381. https://doi.org/10.1016/0013-4694(70)90230-0
Logan RW, Williams WP, McClung CA (2014) Circadian rhythms and addiction: mechanistic insights and future directions. Behav Neurosci 128:387–412. https://doi.org/10.1037/a0036268
Luo YJ, Li YD, Wang L, Yang SR, Yuan XS, Wang J, Cherasse Y, Lazarus M, Chen JF, Qu WM, Huang ZL (2018) Nucleus accumbens controls wakefulness by a subpopulation of neurons expressing dopamine D1 receptors. Nat Commun 9:1576. https://doi.org/10.1038/s41467-018-03889-3
Lydon-Staley DM, Cleveland HH, Huhn AS et al (2017) Daily sleep quality affects drug craving, partially through indirect associations with positive affect, in patients in treatment for nonmedical use of prescription drugs. Addict Behav 65:275–282. https://doi.org/10.1016/j.addbeh.2016.08.026
Maulik PK, Tripathi BM, Pal HR (2002) Coping behaviors and relapse participants in opioid dependence: a study from North India. J Subst Abuse Treat. 22:135–140. https://doi.org/10.1016/s0740-5472(02)00225-8
Montandon G, Horner RL (2019) Electrocortical changes associating sedation and respiratory depression by the opioid analgesic fentanyl. Sci Rep 9:14122. https://doi.org/10.1038/s41598-019-50613-2
Morisot N, Contarino A (2016) The CRF1 and the CRF2 receptor mediate recognition memory deficits and vulnerability induced by opiate withdrawal. Neuropharmacol 105:500–507. https://doi.org/10.1016/j.neuropharm.2016.02.021
O’Donnell JK, Halpin J, Mattson CL et al (2017) Deaths Involving Fentanyl, Fentanyl Analogs, and U-47700 — 10 States, July–December 2016. MMWR Morb Mortal Wkly Rep 66:1197–1202. https://doi.org/10.15585/mmwr.mm6643e1
O’Donnell BJ, Guo L, Ghosh S et al (2019) Sleep phenotype in the Townes mouse model of sickle cell disease. Sleep Breath 23:333–339. https://doi.org/10.1007/s11325-018-1711-x
Orr WC, Stahl ML (1978) Sleep Patterns in human methadone addiction. Addiction 73:311–315. https://doi.org/10.1111/j.1360-0443.1978.tb00158.x
Oswald I (1969) Sleep, dreaming and drugs. Proc R Soc Med 62:151–153
Ozburn AR, Falcon E, Twaddle A et al (2015) Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2. Biol Psychiatry 77:425–433. https://doi.org/10.1016/j.biopsych.2014.07.030
Ozburn AR, Kern J, Parekh PK, Logan RW, Liu Z, Falcon E, Becker-Krail D, Purohit K, Edgar NM, Huang Y, McClung CA (2017) NPAS2 regulation of anxiety-like behavior and GABAA receptors. Front Mol Neurosci 10:360. https://doi.org/10.3389/fnmol.2017.00360
Parekh PK, Logan RW, Ketchesin KD, Becker-Krail D, Shelton MA, Hildebrand MA, Barko K, Huang YH, McClung CA (2019) Cell-type-specific regulation of nucleus accumbens synaptic plasticity and cocaine reward sensitivity by the circadian protein, NPAS2. J Neurosci 39:4657–4667. https://doi.org/10.1523/JNEUROSCI.2233-18.2019
Peppin JF, Raffa RB, Schatman ME (2020) The polysubstance overdose-death crisis. J Pain Res 13:3405–3408. https://doi.org/10.2147/JPR.S295715
Rapeli P, Kivisaari R, Autti T et al (2006) Cognitive function during early abstinence from opioid dependence: a comparison to age, gender, and verbal intelligence matched controls. BMC Psychiatry 6:9. https://doi.org/10.1186/1471-244X-6-9
Shaw IR, Lavigne G, Mayer P, Choinière M (2005) Acute intravenous administration of morphine perturbs sleep architecture in healthy pain-free young adults: a preliminary study. Sleep 28:677–682. https://doi.org/10.1093/sleep/28.6.677
Smith MT, Mun CJ, Remeniuk B et al (2020) Experimental sleep disruption attenuates morphine analgesia: findings from a randomized trial and implications for the opioid abuse epidemic. Sci Rep 10:20121. https://doi.org/10.1038/s41598-020-76934-1
Stein MD, Herman DS, Bishop S, Lassor JA, Weinstock M, Anthony J, Andersen BJ (2004) Sleep disturbances among methadone maintained patients. J Subst Abuse Treat 26:175–180. https://doi.org/10.1016/S0740-5472(03)00191-0
Tagaito Y, Polotsky VY, Campen MJ et al (2001) A model of sleep-disordered breathing in the C57BL/6J mouse. J Appl Physiol 91:2758–2766. https://doi.org/10.1152/jappl.2001.91.6.2758
Tripathi R, Rao R, Dhawan A et al (2020) Opioids and sleep – a review of literature. Sleep Med 67:269–275. https://doi.org/10.1016/j.sleep.2019.06.012
Veasey SC, Yeou-Jey H, Thayer P, Fenik P (2004) Murine multiple sleep latency test: phenotyping sleep propensity in Mice. Sleep 27:388–393. https://doi.org/10.1093/sleep/27.3.388
Wang D, Teichtahl H (2007) Opioids, sleep architecture and sleep-disordered breathing. Sleep Med Rev 11:35–46. https://doi.org/10.1016/j.smrv.2006.03.006
Zhang R, Manza P, Tomasi D, Kim SW, Shokri-Kojori E, Demiral SB, Kroll DS, Feldman DE, McPherson KL, Biesecker CL, Wang GJ, Volkow ND (2021) Dopamine D1 and D2 receptors are distinctly associated with rest-activity rhythms and drug reward. J Clin Invest 131:e149722. https://doi.org/10.1172/JCI149722
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This study was funded by NHLBI R01HL150432 to R.W.L.
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Gamble, M.C., Chuan, B., Gallego-Martin, T. et al. A role for the circadian transcription factor NPAS2 in the progressive loss of non-rapid eye movement sleep and increased arousal during fentanyl withdrawal in male mice. Psychopharmacology 239, 3185–3200 (2022). https://doi.org/10.1007/s00213-022-06200-x
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DOI: https://doi.org/10.1007/s00213-022-06200-x