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Journal of Pharmacology and Experimental Therapeutics

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OtherANALGESIA AND DRUGS OF ABUSE

Protein Kinase A Maintains Cellular Tolerance toMu Opioid Receptor Agonists in Hypothalamic Neurosecretory Cells with Chronic Morphine Treatment: Convergence on a Common Pathway with Estrogen in Modulating Mu Opioid Receptor/Effector Coupling

Edward J. Wagner, Oline K. Rønnekleiv and Martin J. Kelly
Journal of Pharmacology and Experimental Therapeutics June 1998, 285 (3) 1266-1273;
Edward J. Wagner
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Oline K. Rønnekleiv
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Martin J. Kelly
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Abstract

The present study examined protein kinase A (PKA) and protein kinase C (PKC) involvement in the maintenance of cellular tolerance tomu opioid receptor agonists resulting from chronic opiate exposure in neurosecretory cells of the hypothalamic arcuate nucleus (ARC). The possibility that the diminution of muopioid receptor/effector coupling produced by acute 17β-estradiol or chronic opiate exposures is mediated by a common kinase pathway also was investigated. Intracellular recordings were made in hypothalamic slices prepared from ovariectomized female guinea pigs. Themu opioid receptor agonistd-Ala2, N-Me-Phe4, Gly-ol5-enkephalin (DAMGO) produced dose-dependent hyperpolarizations of ARC neurons. Chronic morphine treatment for 4 days reduced DAMGO potency 2.5-fold with no change in the maximal response. This effect was mimicked by a 20-min bath application of the PKA activator cAMP, Sp-isomer, or the PKC activator phorbol-12,13-dibutyrate. A 30-min bath application of the broad-spectrum protein kinase inhibitor staurosporine completely abolished the reduced DAMGO potency seen in morphine-tolerant neurosecretory cells, including those immunopositive for gonadotropin-releasing hormone. The effect of staurosporine was mimicked by the PKA inhibitor cAMP, Rp-isomer, but not by the PKC inhibitor calphostin C. Finally, a 20-min bath application of 17β-estradiol did not further reduce DAMGO potency in morphine-tolerant ARC neurons. Therefore, increased PKA activity maintains cellular tolerance to mu opioid receptor agonists in ARC neurosecretory cells caused by chronic morphine treatment. Furthermore, acute 17β-estradiol and chronic opiate treatments attenuate mu opioid receptor-mediated responses via a common PKA pathway.

Footnotes

  • Send reprint requests to: Edward J. Wagner, Ph.D., Dept. of Physiology & Pharmacology, L334, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201.

  • ↵1 The experiments described in this study were supported by PHS Grants DA05158 and DA00192 (RSDA to M.J.K.).

  • ↵2 Supported by PHS training grants 5T32 DA07262 and 5T32 HD07133.

  • Abbreviations:
    ANOVA
    analysis of variance
    ARC
    arcuate nucleus
    cAMP
    cyclic adenosine monophosphate
    DAMGO
    d-Ala2, N-Me-Phe4, Gly-ol5-enkephalin
    Δg
    increase in conductance
    ΔVmax
    maximum steady-state hyperpolarization
    E2
    17β-estradiol
    FITC
    fluorescein isothiocyanate
    GnRH
    gonadotropin-releasing hormone
    HAP
    hyperpolarizing after potential
    LSD
    least significant difference
    PDBu
    phorbol-12,13-dibutyrate
    PKA
    protein kinase A
    PKC
    protein kinase C
    Rp-cAMP
    adenosine 3′,5′-cyclic monophosphothioate, Rp-isomer
    Sp-cAMP
    adenosine 3′,5′-cyclic monophosphothioate, Sp-isomer
    τ
    membrane time constant
    TH
    tyrosine hydroxylase
    TTX
    tetrodotoxin
    V/I
    voltage-current
    Vm
    membrane potential
    HEPES
    N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
    aCSF
    artificial cerebrospinal fluid
    • Received October 17, 1997.
    • Accepted February 13, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 3
1 Jun 1998
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Protein Kinase A Maintains Cellular Tolerance toMu Opioid Receptor Agonists in Hypothalamic Neurosecretory Cells with Chronic Morphine Treatment: Convergence on a Common Pathway with Estrogen in Modulating Mu Opioid Receptor/Effector Coupling
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OtherANALGESIA AND DRUGS OF ABUSE

Protein Kinase A Maintains Cellular Tolerance toMu Opioid Receptor Agonists in Hypothalamic Neurosecretory Cells with Chronic Morphine Treatment: Convergence on a Common Pathway with Estrogen in Modulating Mu Opioid Receptor/Effector Coupling

Edward J. Wagner, Oline K. Rønnekleiv and Martin J. Kelly
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1266-1273;

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OtherANALGESIA AND DRUGS OF ABUSE

Protein Kinase A Maintains Cellular Tolerance toMu Opioid Receptor Agonists in Hypothalamic Neurosecretory Cells with Chronic Morphine Treatment: Convergence on a Common Pathway with Estrogen in Modulating Mu Opioid Receptor/Effector Coupling

Edward J. Wagner, Oline K. Rønnekleiv and Martin J. Kelly
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1266-1273;
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