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Research ArticleArticle

Mechanisms of the Inhibition of Nuclear Factor-κB by Morphine in Neuronal Cells

Christine Börner, Volker Höllt and Jürgen Kraus
Molecular Pharmacology April 2012, 81 (4) 587-597; DOI: https://doi.org/10.1124/mol.111.076620
Christine Börner
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Volker Höllt
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Jürgen Kraus
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Abstract

Opioids potently modulate neuronal functions, for example, by regulating the activity of transcription factors. Here, we investigated the effect of morphine on the activity of the transcription factor nuclear factor κB (NF-κB). Establishing cellular models for our investigations, we demonstrated that NF-κB mediated the tumor necrosis factor (TNF)-induced transcription of the cannabinoid receptor type 1 gene in primary fetal striatal neurons from rats and the human neuroblastoma cell line SH SY5Y. The activity of NF-κB in these models was strongly inhibited by morphine, which was achieved by a marked up-regulation of the inhibitor of nuclear factor-κB (IκB). The opioid-induced up-regulation of IκB was dependent on the transcription factors NF-κB itself and activator protein-1 (AP-1). In fact, stimulation of the cells with morphine resulted in a transient activation of NF-κB and a strong induction of c-Fos, one of the constituents of AP-1. This resulted in IκB levels significantly exceeding the basal, constitutive levels of IκB. These data, together with experiments in which AP-1 and IκB were down-regulated by decoy oligonucleotides and siRNA, suggest that the morphine-induced activation of AP-1 and the subsequent overexpression of IκB are key factors in the inhibition of NF-κB by the drug. In contrast, stimulation of primary neurons from rats and SH SY5Y cells with TNF, which is a classic activator of NF-κB, resulted in a resynthesis of IκB, in which the basal levels of IκB were restored only but did not result in an activation of AP-1 and overexpression of IκB.

Footnotes

  • This work was supported by the Deutsche Forschungsgemeinschaft [Grant KR 1740/10-1].

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

    http://dx.doi.org/10.1124/mol.111.076620.

  • ABBREVIATIONS:

    NF-κB
    nuclear factor κB
    CB1
    cannabinoid receptor type 1
    TNF
    tumor necrosis factor
    PMA
    phorbol 12-myristate 13-acetate
    cAMPS-RP
    adenosine-3′,5′-cyclic monophosphorothioate, Rp-isomer
    CTAP
    d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2
    H-89
    N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline
    PD98059
    2′-amino-3′-methoxyflavone
    SB203580
    4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene
    ZM336372
    3-(dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]-benzamide
    MAPK
    mitogen-activated protein kinase
    PKA
    protein kinase A
    PCR
    polymerase chain reaction
    RT-PCR
    reverse transcription-polymerase chain reaction
    IκB
    inhibitor of nuclear factor-κB
    CAT
    chloramphenicol acetyltransferase
    ELISA
    enzyme-linked immunosorbent assay
    PTX
    pertussis toxin.

  • Received October 28, 2011.
  • Accepted January 18, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (4)
Molecular Pharmacology
Vol. 81, Issue 4
1 Apr 2012
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Research ArticleArticle

Inhibition of NF-κB by Morphine

Christine Börner, Volker Höllt and Jürgen Kraus
Molecular Pharmacology April 1, 2012, 81 (4) 587-597; DOI: https://doi.org/10.1124/mol.111.076620

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Research ArticleArticle

Inhibition of NF-κB by Morphine

Christine Börner, Volker Höllt and Jürgen Kraus
Molecular Pharmacology April 1, 2012, 81 (4) 587-597; DOI: https://doi.org/10.1124/mol.111.076620
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