BACKGROUND AND PURPOSE: Opioids affect the circadian clock and may change the timing of many physiological processes. This study was undertaken to investigate the daily changes in sensitivity of the circadian pacemaker to an analgesic dose of morphine, and to uncover a possible interplay between circadian and opioid signalling. EXPERIMENTAL APPROACH: A time-dependent effect of morphine (1 mg·kg(-1) , i.p.) applied either during the day or during the early night was followed, and the levels of phosphorylated ERK1/2, GSK3β, c-Fos and Per genes were assessed by immunohistochemistry and in situ hybridization. The effect of morphine pretreatment on light-induced pERK and c-Fos was examined, and day/night difference in activity of opioid receptors was evaluated by [(35) S]-GTPγS binding assay. KEY RESULTS: Morphine stimulated a rise in pERK1/2 and pGSK3β levels in the suprachiasmatic nucleus (SCN) when applied during the day but significantly reduced both kinases when applied during the night. Morphine at night transiently induced Period1 but not Period2 in the SCN and did not attenuate the light-induced level of pERK1/2 and c-Fos in the SCN. The activity of all three principal opioid receptors was high during the day but decreased significantly at night, except for the δ receptor. Finally, we demonstrated daily profiles of pERK1/2 and pGSK3β levels in the rat ventrolateral and dorsomedial SCN. CONCLUSIONS AND IMPLICATIONS: Our data suggest that the phase-shifting effect of opioids may be mediated via post-translational modification of clock proteins by means of activated ERK1/2 and GSK3β.

Faculty of Science Charles University Prague Czech Republic

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Akiyama M, Kouzu Y, Takahashi S, Wakamatsu H, Moriya T, Maetani M, et al. Inhibition of light- or glutamate-induced mPer1 expression represses the phase shifts into the mouse circadian locomotor and suprachiasmatic firing rhythms. J Neurosci. 1999;19:1115–1121. PubMed PMC

Albrecht U, Sun ZS, Eichele G, Lee CC. A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light. Cell. 1997;9:1055–1064. PubMed

Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, et al. The Concise Guide to PHARMACOLOGY 2013/14: G protein-coupled receptors. Br J Pharmacol. 2013a;170:1459–1581. PubMed PMC

Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, et al. The Concise Guide to PHARMACOLOGY 2013/14: nuclear hormone receptors. Br J Pharmacol. 2013b;170:1652–1675. PubMed PMC

Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, et al. The Concise Guide to PHARMACOLOGY 2013/14: enzymes. Br J Pharmacol. 2013c;170:1797–1867. PubMed PMC

Antle MC, Kriegsfeld LJ, Silver R. Signaling within the master clock of the brain: localized activation of mitogen-activated protein kinase by gastrin-releasing peptide. J Neurosci. 2005a;25:2447–2454. PubMed PMC

Antle MC, LeSauter J, Silver R. Neurogenesis and ontogeny of specific cell phenotypes within the hamster suprachiasmatic nucleus. Brain Res Dev Brain Res. 2005b;157:8–18. PubMed PMC

Antle MC, Tse F, Koke SJ, Sterniczuk R, Hagel K. Non-photic phase shifting of the circadian clock: role of the extracellular signal-responsive kinases I/II/mitogen-activated protein kinase pathway. Eur J Neurosci. 2008;28:2511–2518. PubMed

Berhow MT, Hiroi N, Nestler EJ. Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine. J Neurosci. 1996;16:4707–4715. PubMed PMC

Boom M, Grefkens J, van Dorp E, Olofsen E, Lourenssen G, Aarts L, et al. Opioid chronopharmacology: influence of timing of infusion on fentanyl's analgesic efficacy in healthy human volunteers. J Pain Res. 2010;21:183–190. PubMed PMC

Borgkvist A, Usiello A, Greengard P, Fisone G. Activation of the cAMP/PKA/DARPP-32 signaling pathway is required for morphine psychomotor stimulation but not for morphine reward. Neuropsychopharmacology. 2007;32:1995–2003. PubMed

Buhr ED, Takahashi JS. Molecular components of the mammalian circadian clock. Handb Exp Pharmacol. 2013;217:3–27. PubMed PMC

Byku M, Gannon RL. SNC 80, a delta-opioid agonist, elicits phase advances in hamster circadian activity rhythms. Neuroreport. 2000a;11:1449–1452. PubMed

Byku M, Gannon RL. Opioid induced non-photic phase shifts of hamster circadian activity rhythms. Brain Res. 2000b;873:189–196. PubMed

Byku M, Legutko R, Gannon RL. Distribution of delta opioid receptor immunoreactivity in the hamster suprachiasmatic nucleus and intergeniculate leaflet. Brain Res. 2000;857:1–7. PubMed

Chen JC, Smith ER, Cahill M, Cohen R, Fishman JB. The opioid receptor binding of dezocine, morphine, fentanyl, butorphanol and nalbuphine. Life Sci. 1993;52:389–396. PubMed

Cutler DJ, Mundey MK, Mason R. Electrophysiological effects of opioid receptor activation on Syrian hamster suprachiasmatic nucleus neurones in vitro. Brain Res Bull. 1999;50:119–125. PubMed

Dehpour AR, Farsam H, Azizabadi-Farahani M. The effect of lithium on morphine-induced analgesia in mice. Gen Pharmacol. 1994;25:1635–1641. PubMed

Desjardins GC, Brawer JR, Beaudet A. Distribution of mu, delta, and kappa opioid receptors in the hypothalamus of the rat. Brain Res. 1990;536:114–123. PubMed

Dimsdale JE, Norman D, DeJardin D, Wallace MS. The effect of opioids on sleep architecture. J Clin Sleep Med. 2007;3:33–36. PubMed

Ding YQ, Kaneko T, Nomura S, Mizuno N. Immunohistochemical localization of mu-opioid receptors in the central nervous system of the rat. J Comp Neurol. 1996;367:375–402. PubMed

Dziema H, Oatis B, Butcher GQ, Yates R, Hoyt KR, Obrietan K. The ERK/MAP kinase pathway couples light to immediate-early gene expression in the suprachiasmatic nucleus. Eur J Neurosci. 2003;17:1617–1627. PubMed

Eitan S, Bryant CD, Saliminejad N, Yang YC, Vojdani E, Keith D, Jr, et al. Brain region-specific mechanisms for acute morphine-induced mitogen-activated protein kinase modulation and distinct patterns of activation during analgesic tolerance and locomotor sensitization. J Neurosci. 2003;23:8360–8369. PubMed PMC

Fukuhara C, Brewer JM, Dirden JC, Bittman EL, Tosini G, Harrington ME. Neuropeptide Y rapidly reduces Period 1 and Period 2 mRNA levels in the hamster suprachiasmatic nucleus. Neurosci Lett. 2001;314:119–122. PubMed

Guillaumond F, Becquet D, Blanchard MP, Attia J, Moreno M, Bosler O, et al. Nocturnal expression of phosphorylated-ERK1/2 in gastrin-releasing peptide neurons of the rat suprachiasmatic nucleus. J Neurochem. 2007;101:1224–1235. PubMed

Harada Y, Sakai M, Kurabayashi N, Hirota T, Fukada Y. Ser-557-phosphorylated mCRY2 is degraded upon synergistic phosphorylation by glycogen synthase kinase-3 beta. J Biol Chem. 2005;280:31714–31721. PubMed

Horikawa K, Yokota S, Fuji K, Akiyama M, Moriya T, Okamura H, et al. Nonphotic entrainment by 5-HT1A/7 receptor agonists accompanied by reduced Per1 and Per2 mRNA levels in the suprachiasmatic nuclei. J Neurosci. 2000;20:5867–5873. PubMed PMC

Iitaka C, Miyazaki K, Akaike T, Ishida N. A role for glycogen synthase kinase-3beta in the mammalian circadian clock. J Biol Chem. 2005;280:29397–29402. PubMed

Kalsbeek A, Fliers E, Hofman MA, Swaab DF, Buijs RM. Vasopressin and the output of the hypothalamic biological clock. J Neuroendocrinol. 2010;22:362–372. PubMed

Karatsoreos IN, Yan L, LeSauter J, Silver R. Phenotype matters: identification of light-responsive cells in the mouse suprachiasmatic nucleus. J Neurosci. 2004;24:68–75. PubMed PMC

Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol. 2010;160:1577–1579. PubMed PMC

Ko CH, Takahashi JS. Molecular components of the mammalian circadian clock. Hum Mol Genet. 2006;15:R271–R277. PubMed

Ko HW, Kim EY, Chiu J, Vanselow JT, Kramer A, Edery I. A hierarchical phosphorylation cascade that regulates the timing of PERIOD nuclear entry reveals novel roles for proline-directed kinases and GSK-3beta/SGG in circadian clocks. J Neurosci. 2010;30:12664–12675. PubMed PMC

Lambert CM, Machida KK, Smale L, Nunez AA, Weaver DR. Analysis of the prokineticin 2 system in a diurnal rodent, the unstriped Nile grass rat (Arvicanthis niloticus. J Biol Rhythms. 2005;20:206–218. PubMed

Lavoie J, Hébert M, Beaulieu JM. Glycogen synthase kinase-3β haploinsufficiency lengthens the circadian locomotor activity period in mice. Behav Brain Res. 2013;253:262–265. PubMed

Li LY, Chang KJ. The stimulatory effect of opioids on mitogen-activated protein kinase in Chinese hamster ovary cells transfected to express mu-opioid receptors. Mol Pharmacol. 1996;50:599–602. PubMed

Liu J, Nickolenko J, Sharp FR. Morphine induces c-fos and junB in striatum and nucleus accumbens via D1 and N-methyl-D-aspartate receptors. Proc Natl Acad Sci U S A. 1994;91:8537–8541. PubMed PMC

Mansour A, Fox CA, Burke S, Meng F, Thompson RC, Akil H, et al. Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study. J Comp Neurol. 1994;350:412–438. PubMed

Marchant EG, Mistlberger RE. Morphine phase-shifts circadian rhythms in mice: role of behavioural activation. Neuroreport. 1995;7:209–712. PubMed

Maywood ES, Mrosovsky N, Field MD, Hastings MH. Rapid down-regulation of mammalian period genes during behavioral resetting of the circadian clock. Proc Natl Acad Sci U S A. 1999;96:15211–15216. PubMed PMC

McCarthy MJ, Nievergelt CM, Kelsoe JR, Welsh DK. A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response. PLoS ONE. 2012;7:e32091. PubMed PMC

McGrath J, Drummond G, McLachlan E, Kilkenny C, Wainwright C. Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br J Pharmacol. 2010;160:1573–1576. PubMed PMC

Meijer JH, Ruijs AC, Albus H, van de Geest B, Duindam H, Zwinderman AH, et al. Fentanyl, a upsilon-opioid receptor agonist, phase shifts the hamster circadian pacemaker. Brain Res. 2000;868:135–140. PubMed

Merighi S, Gessi S, Varani K, Fazzi D, Stefanelli A, Borea PA. Morphine mediates a proinflammatory phenotype via μ-opioid receptor-PKCε-Akt-ERK1/2 signaling pathway in activated microglial cells. Biochem Pharmacol. 2013;86:487–496. PubMed

Morin LP. SCN organization reconsidered. J Biol Rhythms. 2007;22:3–13. PubMed

Naber D, Cohen RM, Pickar D, Kalin NH, Davis G, Pert CB, et al. Episodic secretion of opioid activity in human plasma and monkey CSF: evidence for a diurnal rhythm. Life Sci. 1981;28:931–935. PubMed

Nakaya M, Sanada K, Fukada Y. Spatial and temporal regulation of mitogen-activated protein kinase phosphorylation in the mouse suprachiasmatic nucleus. Biochem Biophys Res Commun. 2003;305:494–501. PubMed

Obrietan K, Impey S, Storm DR. Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nat Neurosci. 1998;1:693–700. PubMed

Ortiz J, Harris HW, Guitart X, Terwilliger RZ, Haycock JW, Nestler EJ. Extracellular signal-regulated protein kinases (ERKs) and ERK kinase (MEK) in brain: regional distribution and regulation by chronic morphine. J Neurosci. 1995;15:1285–1297. PubMed PMC

Osland TM, Fernø J, Håvik B, Heuch I, Ruoff P, Lærum OD, et al. Lithium differentially affects clock gene expression in serum-shocked NIH-3T3 cells. J Psychopharmacol. 2011;25:924–933. PubMed

Pawson AJ, Sharman JL, Benson HE, Faccenda E, Alexander SP, Buneman OP, et al. NC-IUPHAR. The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledgebase of drug targets and their ligands. Nucl Acids Res. 2014;42:D1098–D1106. (Database Issue): PubMed PMC

Raffa RB, Martinez RP, Renzi MJ, Codd EE. LiCl uncouples signal transduction in morphine-induced supraspinal antinociception in mice. Gen Pharmacol. 1995;26:317–320. PubMed

Raymond RC, Warren M, Morris RW, Leikin JB. Periodicity of presentations of drugs of abuse and overdose in an emergency department. J Toxicol Clin Toxicol. 1992;30:467–478. PubMed

Reischl S, Kramer A. Kinases and phosphatases in the mammalian circadian clock. FEBS Lett. 2011;585:1393–1399. PubMed

Sahar S, Zocchi L, Kinoshita C, Borrelli E, Sassone-Corsi P. Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation. PLoS ONE. 2010;5:e8561. PubMed PMC

Sanada K, Okano T, Fukada Y. Mitogen-activated protein kinase phosphorylates and negatively regulates basic helix-loop-helix-PAS transcription factor BMAL1. J Biol Chem. 2002;277:267–271. PubMed

Sanada K, Harada Y, Sakai M, Todo T, Fukada Y. Serine phosphorylation of mCRY1 and mCRY2 by mitogen-activated protein kinase. Genes Cells. 2004;9:697–708. PubMed

Shaw IR, Lavigne G, Mayer P, Choinière M. Acute intravenous administration of morphine perturbs sleep architecture in healthy pain-free young adults: a preliminary study. Sleep. 2005;28:677–682. PubMed

Sládek M, Sumová A, Kováciková Z, Bendová Z, Laurinová K, Illnerová H. Insight into molecular core clock mechanism of embryonic and early postnatal rat suprachiasmatic nucleus. Proc Natl Acad Sci U S A. 2004;101:6231–6236. PubMed PMC

Tierno A, Fiore P, Gannon RL. Delta opioid inhibition of light-induced phase advances in hamster circadian activity rhythms. Brain Res. 2002;937:66–73. PubMed

Trávníčková Z, Sumová A, Peters R, Schwartz WJ, Illnerová H. Photoperiod-dependent correlation between light-induced SCN c-fos expression and resetting of circadian phase. Am J Physiol. 1996;271:R825–R831. PubMed

Vansteensel MJ, Deboer T, Dahan A, Meijer JH. Differential responses of circadian activity onset and offset following GABA-ergic and opioid receptor activation. J Biol Rhythms. 2003;18:297–306. PubMed

Vansteensel MJ, Magnone MC, van Oosterhout F, Baeriswyl S, Albrecht U, Albus H, et al. The opioid fentanyl affects light input, electrical activity and Per gene expression in the hamster suprachiasmatic nuclei. Eur J Neurosci. 2005;21:2958–2966. PubMed

Wang YJ, Rasakham K, Huang P, Chudnovskaya D, Cowan A, Liu-Chen LY. Sex difference in κ-opioid receptor (KOPR)-mediated behaviors, brain region KOPR level and KOPR-mediated guanosine 5'-O-(3-[35S]thiotriphosphate) binding in the guinea pig. J Pharmacol Exp Ther. 2011;339:438–450. PubMed PMC

Yoshida M, Ohdo S, Takane H, Tomiyoshi Y, Matsuo A, Yukawa E, et al. Chronopharmacology of analgesic effect and its tolerance induced by morphine in mice. J Pharmacol Exp Ther. 2003;305:1200–1205. PubMed

Zylka MJ, Shearman LP, Weaver DR, Reppert SM. Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron. 1998;20:1103–1110. PubMed

The day/night difference in the circadian clock's response to acute lipopolysaccharide and the rhythmic Stat3 expression in the rat suprachiasmatic nucleus

Delayed Effect of the Light Pulse on Phosphorylated ERK1/2 and GSK3β Kinases in the Ventrolateral Suprachiasmatic Nucleus of Rat