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Research ArticleCellular and Molecular

Morphine Withdrawal Activates Hypothalamic-Pituitary-Adrenal Axis and Heat Shock Protein 27 in the Left Ventricle: The Role of Extracellular Signal-Regulated Kinase

E. Martínez-Laorden, M. A. Hurle, M. V. Milanés, M. L. Laorden and P. Almela
Journal of Pharmacology and Experimental Therapeutics September 2012, 342 (3) 665-675; DOI: https://doi.org/10.1124/jpet.112.193581
E. Martínez-Laorden
Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain (E.M.-L., M.V.M., M.L.L., P.A.); and Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain (M.A.H.)
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M. A. Hurle
Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain (E.M.-L., M.V.M., M.L.L., P.A.); and Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain (M.A.H.)
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M. V. Milanés
Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain (E.M.-L., M.V.M., M.L.L., P.A.); and Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain (M.A.H.)
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M. L. Laorden
Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain (E.M.-L., M.V.M., M.L.L., P.A.); and Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain (M.A.H.)
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P. Almela
Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain (E.M.-L., M.V.M., M.L.L., P.A.); and Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain (M.A.H.)
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This article has a correction. Please see:

  • Correction to: “Morphine Withdrawal Activates Hypothalamic-Pituitary Adrenal Axis and Heat Shock Protein 27 in the Left Ventricle: The Role of Extracellular Signal-Regulated Kinase” - February 01, 2013

Abstract

The negative affective states of withdrawal involve the recruitment of brain and peripheral stress circuitry [e.g., noradrenergic activity, induction of the hypothalamo-pituitary-adrenocortical (HPA) axis, and the expression and activation of heat shock proteins (Hsps)]. The present study investigated the role of extracellular signal-regulated protein kinase (ERK) and β-adrenoceptor on the response of stress systems to morphine withdrawal by the administration of [amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile (SL327), a selective inhibitor of ERK activation, or propranolol (a β-adrenoceptor antagonist). Dependence on morphine was induced by a 7-day subcutaneous implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by the injection of naloxone (2 mg/kg s.c.). Plasma concentrations of adrenocorticotropin and corticosterone were determined by radioimmunoassay; noradrenaline (NA) turnover in left ventricle was determined by high-performance liquid chromatography; and catechol-O-methyl transferase (COMT) and Hsp27 expression and phosphorylation at Ser82 were determined by quantitative blot immunolabeling. Morphine-withdrawn rats showed an increase of NA turnover and COMT expression in parallel with an enhancement of adrenocorticotropin and plasma corticosterone concentrations. In addition, we observed an enhancement of Hsp27 expression and phosphorylation. Pretreatment with SL327 or propranolol significantly reduced morphine withdrawal-induced increases of plasma adrenocorticotropin and Hsp27 phosphorylation at Ser82 without any changes in plasma corticosterone levels. The present findings demonstrate that morphine withdrawal is capable of inducing the activation of HPA axis in parallel with an enhancement of Hsp27 expression and Hsp27 phosphorylation at Ser82 and suggest a role for β-adrenoceptors and ERK pathways in mediating morphine-withdrawal activation of the HPA axis and cellular stress response.

Footnotes

  • This work was supported by the Ministerio de Ciencia e Innovación [Grants SAF/FEDER (El Fondo Europeo de Desarrollo Regional) 2009-07178, 2010-17907]; and Red de Trastornos Adictivos [Grant RD06/0001/1006].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.193581.

  • ABBREVIATIONS:

    HPA
    hypothalamo-pituitary-adrenocortical
    ANOVA
    analysis of variance
    COMT
    catechol-O-methyl transferase
    MB-COMT
    membrane COMT
    S-COMT
    soluble COMT
    CRF
    corticotrophin-releasing factor
    ERK
    extracellular signal-regulated protein kinase
    pERK
    phospho-ERK
    HPLC
    high-performance liquid chromatography
    Hsp
    heat shock protein
    pHsp
    phospho-Hsp
    NA
    noradrenaline
    NMN
    normetanephrine
    PVN
    paraventricular nucleus
    SL327
    α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile
    TBST
    Tris buffer saline Tween.

  • Received February 23, 2012.
  • Accepted May 29, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 3
1 Sep 2012
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Research ArticleCellular and Molecular

HPA Adrenal Axis and Hsp27 during Morphine Withdrawal

E. Martínez-Laorden, M. A. Hurle, M. V. Milanés, M. L. Laorden and P. Almela
Journal of Pharmacology and Experimental Therapeutics September 1, 2012, 342 (3) 665-675; DOI: https://doi.org/10.1124/jpet.112.193581

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Research ArticleCellular and Molecular

HPA Adrenal Axis and Hsp27 during Morphine Withdrawal

E. Martínez-Laorden, M. A. Hurle, M. V. Milanés, M. L. Laorden and P. Almela
Journal of Pharmacology and Experimental Therapeutics September 1, 2012, 342 (3) 665-675; DOI: https://doi.org/10.1124/jpet.112.193581
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