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Molecular Pharmacology

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Research ArticleArticle

Signaling Cascades for δ-Opioid Receptor-Mediated Inhibition of GABA Synaptic Transmission and Behavioral Antinociception

Zhi Zhang and Zhizhong Z. Pan
Molecular Pharmacology March 2012, 81 (3) 375-383; DOI: https://doi.org/10.1124/mol.111.076307
Zhi Zhang
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Zhizhong Z. Pan
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Abstract

Membrane trafficking of the δ-opioid receptor (DOR) from intracellular compartments to plasma membrane in central neurons, induced by various pathological conditions such as long-term opioid exposure, represents unique receptor plasticity involved in the mechanisms of long-term opioid effects in opioid addiction and opioid treatment of chronic pain. However, the signaling pathways coupled to the newly emerged functional DOR in central neurons are largely unknown at present. In this study, we investigated the signaling cascades of long-term morphine-induced DOR for its cellular and behavioral effects in neurons of the rat brainstem nucleus raphe magnus (NRM), a key supraspinal site for opioid analgesia. We found that, among the three phospholipase A2 (PLA2)-regulated arachidonic acid (AA) metabolic pathways of lipoxygenase, cyclooxygenase, and epoxygenase, 12-lipoxygenase of the lipoxygenase pathway primarily mediated DOR inhibition of GABA synaptic transmission, because inhibitors of 12-lipoxygenase as well as lipoxygenases and PLA2 largely blocked the DOR- or AA-induced GABA inhibition in NRM neurons in brainstem slices in vitro. Blockade of the epoxygenase pathway was ineffective, whereas blocking either 5-lipoxygenase of the lipoxygenase pathway or the cyclooxygenase pathway enhanced the DOR-mediated GABA inhibition. Behaviorally in rats in vivo, NRM infusion of 12-lipoxygenase inhibitors significantly reduced DOR-induced antinociceptive effect whereas inhibitors of 5-lipoxygenase and cyclooxygenase augmented the DOR antinociception. These findings suggest the PLA2-AA-12-lipoxygenase pathway as a primary signaling cascade for DOR-mediated analgesia through inhibition of GABA neurotransmission and indicate potential therapeutic benefits of combining 5-lipoxygenase and cyclooxygenase inhibitors for maximal pain inhibition.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA023069, DA027541].

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

    http://dx.doi.org/10.1124/mol.111.076307.

  • ABBREVIATIONS:

    MOR
    μ-opioid receptor
    DOR
    δ-opioid receptor
    GPCR
    G protein-coupled receptor
    AA
    arachidonic acid
    PLA2
    phospholipase A2
    COX
    cyclooxygenase
    LOX
    lipoxygenase
    P450
    cytochrome P450
    NRM
    nucleus raphe magnus
    IPSC
    inhibitory postsynaptic current
    NDGA
    nordihydroguaiaretic acid
    AA-861
    2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-p-benzoquinone
    PD146176
    11-dihydro[1]benzothiopyrano[4,3-b]indole
    mIPSC
    miniature inhibitory postsynaptic current
    HPETE
    hydroperoxyeicosatetraenoic acid
    HETE
    hydroxyeicosatetraenoic acids
    PKA
    protein kinase A
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin.

  • Received October 10, 2011.
  • Accepted December 5, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

δ-Opioid Receptor Signaling

Zhi Zhang and Zhizhong Z. Pan
Molecular Pharmacology March 1, 2012, 81 (3) 375-383; DOI: https://doi.org/10.1124/mol.111.076307

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Research ArticleArticle

δ-Opioid Receptor Signaling

Zhi Zhang and Zhizhong Z. Pan
Molecular Pharmacology March 1, 2012, 81 (3) 375-383; DOI: https://doi.org/10.1124/mol.111.076307
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