Skip to main content

Advertisement

SpringerLink
Log in

Differential involvement of 3′, 5′-cyclic adenosine monophosphate-dependent protein kinase in regulation of Fos and tyrosine hydroxylase expression in the heart after naloxone induced morphine withdrawal

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

We previously demonstrated that morphine withdrawal induced hyperactivity of the heart by the activation of noradrenergic pathways innervating the left and right ventricle, as evaluated by noradrenaline (NA) turnover and Fos expression. We investigated whether cAMP-dependent protein kinase (PKA) plays a role in this process by estimating changes in PKA immunoreactivity and the influence of inhibitor of PKA on Fos protein expression, tyrosine hydroxylase (TH) immunoreactivity levels and NA turnover in the left and right ventricle. Dependence on morphine was induced by a 7-day s.c. implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (5 mg/kg). When opioid withdrawal was precipitated, an increase in PKA immunoreactivity and phospho-CREB (cyclic AMP response element protein) levels were observed in the heart. Moreover, morphine withdrawal induces Fos expression, an enhancement of NA turnover and an increase in the total TH levels. When the selective PKA inhibitor HA-1004 was infused, concomitantly with morphine pellets, it diminished the increase in NA turnover and the total TH levels observed in morphine-withdrawn rats. However, this inhibitor neither modifies the morphine withdrawal induced Fos expression nor the increase of nonphosphorylated TH levels. The present findings indicate that an up-regulated PKA-dependent transduction pathway might contribute to the activation of the cardiac catecholaminergic neurons in response to morphine withdrawal and suggest that Fos is not a target of PKA at heart levels.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Almela P, Cerezo M, Milanés MV, Laorden ML (2006) Role of PKC in regulating of Fos and TH expression after naloxone induced morphine withdrawal in the heart. Naunyn-Schmiedeberg’s Arch Pharmacol 372:374–382

    Article  CAS  Google Scholar 

  • Armour JA (1991) Intrinsic cardiac neurons. J Cardiovasc Electrophysiol 2:331–341

    Article  Google Scholar 

  • Armour JA, Huang MH, Smith FM (1993) Peptidergic modulation of in situ canine intrinsic cardiac neurons. Peptides 14:191–202

    Article  PubMed  CAS  Google Scholar 

  • Benavides M, Laorden ML, Milanés MV (2003) Regulation of tyrosine hydroxylase levels and activity and Fos expression during opioid withdrawal in the hypothalamic PNV and medulla oblongata catecholaminergic cell groups innervating the PVN. Eur J Neurosci 17:103–112

    Article  PubMed  Google Scholar 

  • Benavides M, Laorden ML, Milanés MV (2005) Involvement of 3′,5′-cyclic adenosine monophosphate-dependent protein kinase in regulation of Fos expression and tyrosine hydroxylase levels during morphine withdrawal in the hypothalamic paraventricular nucleus and medulla oblongata catecholaminergic cell groups. J Neurochem 92:246–254

    Article  PubMed  CAS  Google Scholar 

  • Berhow MT, Russel DS, Terwilliger RZ, Beitner-Johnson D, Self DW, Lindsay RM, Nestler EJ (1995) Influence of neurotrophic factors on morphine- and cocaine-induced biochemical changes in the mesolimbic dopamine system. Neuroscience 68:969–979

    Article  PubMed  CAS  Google Scholar 

  • Blendy JA, Maldonado R (1998) Genetic analysis of drug addiction: the role of cAMP response element binding proteins. J Mol Med 76:104–110

    Article  PubMed  CAS  Google Scholar 

  • Boundy VA, Gold SJ, Messer CJ, Chen J, Son JH, Hoh TH, Nestler EJ (1998) Regulation of tyrosine hydroxylase promoter activity by chronic morphine in TH9.0-lacZ transgenic mice. J Neurosci 18:9989–9995

    PubMed  CAS  Google Scholar 

  • Cerezo M, Milanés MV, Laorden ML (2005) Alterations in protein kinase A and different protein kinase C isoforms in the heart during morphine withdrawal. Eur J Pharmacol 522:9–19

    Article  PubMed  CAS  Google Scholar 

  • Chien GL, Mohtadi K, Wolff RA, Van Winkle DM (1999) Naloxone blockade of myocardial ischemic preconditioning does not require central nervous system participation. Basic Res Cardiol 94:136–143

    Article  PubMed  CAS  Google Scholar 

  • Childers SR (1991) Opioid receptor-coupled second messengers systems. Life Sci 48:1991–2003

    Article  PubMed  CAS  Google Scholar 

  • Coven DL, Hu X, Cong L (2003) Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. Am J Physiol 285:E629–E636

    CAS  Google Scholar 

  • Curran E, Akil H, Watson S (1996) Psychomotor stimulant- and opiate-induced c-fos mRNA expression patterns in the rat forebrain: comparisons between acute drug treatment and a drug challenge in sensitised animals. Neurochem Res 21:1425–1435

    Article  PubMed  CAS  Google Scholar 

  • Daniel PB, Walker WH, Habener JF (1998) Cyclic AMP signalling and gene regulation. Annu Rev Nutr 18:353–383

    Article  PubMed  CAS  Google Scholar 

  • Goldspink PH, Russell B (1994) The cAMP response element binding protein is expressed and phosphorylated in cardiac myocytes. Circ Res 74:1042–1049

    PubMed  CAS  Google Scholar 

  • Goldspink PH, Russell B (1996) Physiological role of phosphorylation of the cyclic AMP response element binding protein in rat cardiac nuclei. Cell Tissue Res 285:379–385

    Article  PubMed  CAS  Google Scholar 

  • González-Cuello A, Milanés MV, Castells MT, Laorden ML (2003) Activation c-fos expression in the heart after morphine but not U-50,488H withdrawal. Br J Pharmacol 138:626–633

    Article  PubMed  CAS  Google Scholar 

  • González-Cuello A, Milanés MV, Avíles M, Laorden ML (2004a) Changes in c-fos expression in the rat heart during morphine withdrawal. Involvement of alpha2-adrenoceptors. Naunyn-Schmiedeberg’s Arch Pharmacol 370:17–25

    Article  CAS  Google Scholar 

  • González-Cuello A, Milanés MV, Castells MT, Laorden ML (2004b) Morphine-withdrawal induced c-fos expression in the heart: a peripheral mechanism. Eur J Pharmacol 487:117–124

    Article  PubMed  CAS  Google Scholar 

  • González-Cuello A, Milanés MV, Laorden ML (2004c) Increase of tyrosine hydroxylase levels and activity during morphine withdrawal in the heart. Eur J Pharmacol 506:119–128

    Article  PubMed  CAS  Google Scholar 

  • Haddad GE, Coleman BR, Zhao A, Blackwell KN (2004) Modulation of atrial contraction by PKA and PKC during the compensated phase of eccentric acardiac hypertrophy. Basic Res Cardiol 99:317–327

    Article  PubMed  CAS  Google Scholar 

  • Hardie D, Carling D, Halford N (1994) Roles of the Snf1/Rkin1/AMP-activated protein kinase family in the response to environmental and nutritional stress. Sem Cell Biol 5:409–416

    Article  CAS  Google Scholar 

  • Haycock JW (1990) Phosphorylation of tyrosine hydroxylase in situ at serine 8, 19, 31 and 40. J Biol Chem 265:682–691

    Google Scholar 

  • Hidaka H, Imagaki M, Kawamoto S, Sasaki V (1984) Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase and protein kinase C. Biochemistry 23:5036–5041

    Article  PubMed  CAS  Google Scholar 

  • Huang MH, Smith FM, Armour JA (1993) Amino acids modify the activity of canine intrinsic cardiac neurons involved in cardiac regulation. Am J Physiol 264:H1257–H1282

    Google Scholar 

  • Hussain M, Drago GA, Bhogal M, Colyer J, Orchard CH (1999) Effects of the protein kinase A inhibitor H-89 on Ca2+ regulation in isolated ferret ventricular myocytes. Pflugers Arch 437:529–537

    Article  PubMed  CAS  Google Scholar 

  • Kamp TJ, Hell JW (2000) Regulation of cardiac L-type calcium channels by protein kinase A and protein kinase C. Circ Res 87:1095–1102

    PubMed  CAS  Google Scholar 

  • Kumer SC, Vrana KE (1996) Intricate regulation of tyrosine hydroxylase activity and gene expression. J Neurochem 67:443–462

    Article  PubMed  CAS  Google Scholar 

  • Laorden ML, Castells MT, Martínez MD, Martínez PJ, Milanés MV (2000) Activation of c-fos expression in hypothalamic nuclei by mu- and kappa-receptor agonists. Correlation with catecholaminergic activity in the hypothalamic paraventricular nucleus. Endocrinology 141:1366–1376

    Article  PubMed  CAS  Google Scholar 

  • Laorden ML, Castells MT, Milanés MV (2002) Effects of morphine and morphine withdrawal on brainstem neurons innervating hypothalamic nuclei that control the pituitary–adrenocortical axis in rats. Br J Pharmacol 136:67–75

    Article  PubMed  CAS  Google Scholar 

  • Liu JG, Anand KJ (2001) Protein kinase modulates the cellular adaptations associated with opioid tolerance and dependence. Brains Res Rev 38:1–19

    Article  CAS  Google Scholar 

  • Martínez MD, Milanés MV, Laorden ML (2003) Implication of the signal transduction pathways in the enhancement of noradrenaline turnover induced by morphine withdrawal in the heart. Eur J Pharmacol 471:113–119

    Article  PubMed  CAS  Google Scholar 

  • Meinkoth JL, Alberts AS, Went W, Fantozzi D, Taylor SS, Hagiwara M, Montminy M, Feramisco JR (1993) Signal transduction through the cAMP-dependent protein kinase. Mol Cell Biochem 127:179–186

    Article  PubMed  Google Scholar 

  • Milanés MV, Laorden ML (2000) Changes in catecholaminergic pathways innervating the rat heart ventricle during morphine dependence. Involvement of alpaha1 and alpha2 adrenoreceptors. Eur J Pharmacol 397:311–318

    Article  PubMed  Google Scholar 

  • Milanés MV, Fuente T, Laorden ML (2000) Catecholaminergic activity and 3′,5′-cyclic adenosine monophosphate levels in heart right ventricle after naloxone induced withdrawal. Naunyn-Schmiedeberg’s Arch Pharmacol 361:61–66

    Article  Google Scholar 

  • Milanés MV, Martínez MD, González-Cuello A, Laorden ML (2001) Evidence for a peripheral mechanism in cardiac opioid withdrawal. Naunyn-Schmiedeberg’s Arch Pharmacol 364:193–198

    Article  CAS  Google Scholar 

  • Montminy M (1997) Transcriptional regulation by cyclic AMP. Ann Rev Biochem 66:807–822

    Article  PubMed  CAS  Google Scholar 

  • Morgan JI, Curran T (1991) Stimulus transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Annu Rev Neurosci 14:421–451

    Article  PubMed  CAS  Google Scholar 

  • Muller FU, Boknik P, Horst A, Knapp J, Linck B, Schmitz W, Vahlensieck U, Bohm M, Deng MC, Scheld HH (1995) cAMP response element binding protein is expressed and phosphorylated in the human heart. Circulation 92:2041–2043

    PubMed  CAS  Google Scholar 

  • Muller FU, Boknik P, Knapp J, Luss H, Neummann J, Vahlensieck U, Bohm M, Deng MC, Scheld HH, Schmitz W (1997) Quantification of the cAMP response element binding protein in ventricular nuclear protein from failing and nonfailing human hearts. Biochem Biophys Res Commun 236:351–354

    Article  PubMed  CAS  Google Scholar 

  • Murphy DB, Murphy MB (1999) Opioid antagonists modulation of ischemia-induced ventricular arrhythmias: a peripheral mechanism. J Cardiovasc Pharmacol 33:122–125

    Article  PubMed  CAS  Google Scholar 

  • Nestler EJ (1992) Molecular mechanism of drug addiction. J Neurosci 278:58–63

    Google Scholar 

  • Nestler EJ, Aghajanian CK (1997) Molecular and cellular basis of addiction. Science 278:58–63

    Article  PubMed  CAS  Google Scholar 

  • Rabadán JV, Milanés MV, Laorden ML (1997) Effects of chronic morphine treatment on catecholamines content and mechanical response in the rat heart. J Pharmacol Exp Ther 280:32–37

    PubMed  Google Scholar 

  • Rabadán JV, Milanés MV, Laorden ML (1998) Changes in right atria catecholamines content in naive rats and after naloxone-induced withdrawal. Br J Anaesth 80:354–359

    PubMed  Google Scholar 

  • Russell RR, Li J, Coven DL (2004) AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis and injury. J Clin Invest 114:495–503

    Article  PubMed  CAS  Google Scholar 

  • Schultz JJ, Hsu AK, Gross GJ (1997) Ischemic preconditioning is mediated by a peripheral opioid receptor mechanism in the intact heart. J Mol Cell Cardiol 29:1355–1362

    Article  PubMed  CAS  Google Scholar 

  • Sun LS, Quamina A (2003) Perinatal cocaine exposure stimulates the expression and activation of CREB in the neonatal rat heart. Pediatr Res 53:500–506, 2003

    Article  PubMed  CAS  Google Scholar 

  • Tokuyama F, Feng Y, Wakabayashi H, Ho IK (1995) Possible involvement of protein kinases in physical dependence on opioids: studies using protein kinase inhibitors, H-7 and H-8. Eur J Pharmacol 284:101–107

    Article  PubMed  CAS  Google Scholar 

  • Uhler MD, Chrivia JC, McKinight GS (1986) Evidence for a second isoform of the catalytic subunit of cAMP-dependent protein kinase. J Biol Chem 261:15360–15363

    PubMed  CAS  Google Scholar 

  • Wiechelman KJ, Braund RD, Fitzpatrick JD (1988) Investigation of the bicincinomic acid protein assay: identification of the groups responsible for colour formation. Anal Biochem 175:231–237

    Article  PubMed  CAS  Google Scholar 

  • Williams JT, Christie MJ, Manzoni O (2001) Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 81:299–343

    PubMed  CAS  Google Scholar 

  • Young LH, Li J, Baron JS, Russell RR (2005) AMP-activated protein kinase: a key stress signalling pathway in the heart. Trends Cardiovasc Med 15:110–118

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This work was supported by Ministerio de Ciencia y Tecnología (SAF/FEDER 2002-00763, 2003-00756) Spain.

Author information

Authors and Affiliations

  1. Equip of Cellular and Molecular Pharmacology, University School of Medicine, Murcia, Spain

    Pilar Almela, Manuela Cerezo, A. González-Cuello, M. Victoria Milanés & M. Luisa Laorden

  2. Department of Pharmacology, University School of Medicine, Campus de Espinardo, 30100, Murcia, Spain

    Pilar Almela, Manuela Cerezo, A. González-Cuello, M. Victoria Milanés & M. Luisa Laorden

Authors
  1. Pilar Almela
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manuela Cerezo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. González-Cuello
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Victoria Milanés
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Luisa Laorden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Luisa Laorden.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Almela, P., Cerezo, M., González-Cuello, A. et al. Differential involvement of 3′, 5′-cyclic adenosine monophosphate-dependent protein kinase in regulation of Fos and tyrosine hydroxylase expression in the heart after naloxone induced morphine withdrawal. Naunyn-Schmied Arch Pharmacol 374, 293–303 (2007). https://doi.org/10.1007/s00210-006-0120-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-006-0120-z

Keywords

Search

Navigation