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Research ArticleNEUROPHARMACOLOGY

Orphanin FQ/Nociceptin-Mediated Desensitization of Opioid Receptor-Like 1 Receptor and μ Opioid Receptors Involves Protein Kinase C: A Molecular Mechanism for Heterologous Cross-Talk

Chitra D. Mandyam, Deepak R. Thakker, Jennifer L. Christensen and Kelly M. Standifer
Journal of Pharmacology and Experimental Therapeutics August 2002, 302 (2) 502-509; DOI: https://doi.org/10.1124/jpet.102.033159
Chitra D. Mandyam
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Deepak R. Thakker
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Jennifer L. Christensen
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Kelly M. Standifer
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Abstract

Morphine tolerance in vivo is reduced following blockade of the orphanin FQ/nociceptin (OFQ/N)/opioid receptor-like 1 (ORL1) receptor system, suggesting that OFQ/N contributes to the development of morphine tolerance. We previously reported that a 60-min activation of ORL1 receptors natively expressed in BE(2)-C cells desensitized both μ and ORL1 receptor-mediated inhibition of cAMP. Investigating the mechanism(s) of OFQ/N-mediated μ and ORL1 receptor cross-talk, we found that pretreatment with the protein kinase C inhibitor, chelerythrine chloride (1 μM), blocked OFQ/N-mediated homologous desensitization of ORL1 and heterologous desensitization of μ opioid receptors. Furthermore, depletion of PKC by 12-O-tetradecanoylphorbol-13-acetate exposure (48 h, 1 μM) also prevented OFQ/N-mediated μ and ORL1 desensitization. OFQ/N pretreatment resulted in translocation of PKC-α, G protein-coupled receptor kinase 2 (GRK2) and GRK3 from the cytosol to the membrane, and this translocation was also blocked by chelerythrine. Reduction of GRK2 and GRK3 levels by antisense, but not sense DNA treatment blocks ORL1 and μ receptor desensitization. This suggests that PKC-α is required for GRK2 and GRK3 translocation to the membrane, where GRK can inactivate ORL1 and μ opioid receptors upon rechallenge with the appropriate agonist. Our results demonstrate for the first time the involvement of conventional PKC isozymes in OFQ/N-induced μ-ORL1 cross-talk, and represent a possible mechanism for OFQ/N-induced anti-opioid actions.

Footnotes

  • This work was supported in part by work sponsored by a National Research Service Award (DA14171) to C.D.M. and grants from the Department of Health and Human Services (DA10738) and the Texas Advanced Research Program (003652-0114-1999) to K.M.S.

  • DOI: 10.1124/jpet.102.033159

  • Abbreviations:
    OFQ/N
    orphanin FQ/nociceptin
    ORL1
    opioid receptor-like 1
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
    ERK1/2
    extracellular-regulated kinases 1 and 2
    PKC
    protein kinase C
    MEK-1
    mitogen-activated protein kinase kinase
    GRK
    G-protein receptor kinase
    TPA
    12-O-tetradecanoylphorbol-13-acetate
    4αPDD
    4α-phorbol-12,13-didecanoate
    HBSS
    Hanks' balanced salt solution
    PAGE
    polyacrylamide gel electrophoresis
    PBS
    phosphate-buffered saline
    BSA
    bovine serum albumin
    PMSF
    phenylmethylsulfonyl fluoride
    ODN
    oligodeoxynucleotide
    TBS/T
    Tris-buffered saline/Tween 20
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    ANOVA
    analysis of variance
    DAG
    diacylglycerol
    PKA
    protein kinase A
    PD98059
    4H-1-benzopyran-4-one 2-(2-amino-3-methoxy phenyl)
    H-89
    N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinoline sulfonamide
    • Received January 16, 2002.
    • Accepted April 23, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 2
1 Aug 2002
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Research ArticleNEUROPHARMACOLOGY

Orphanin FQ/Nociceptin-Mediated Desensitization of Opioid Receptor-Like 1 Receptor and μ Opioid Receptors Involves Protein Kinase C: A Molecular Mechanism for Heterologous Cross-Talk

Chitra D. Mandyam, Deepak R. Thakker, Jennifer L. Christensen and Kelly M. Standifer
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 502-509; DOI: https://doi.org/10.1124/jpet.102.033159

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Research ArticleNEUROPHARMACOLOGY

Orphanin FQ/Nociceptin-Mediated Desensitization of Opioid Receptor-Like 1 Receptor and μ Opioid Receptors Involves Protein Kinase C: A Molecular Mechanism for Heterologous Cross-Talk

Chitra D. Mandyam, Deepak R. Thakker, Jennifer L. Christensen and Kelly M. Standifer
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 502-509; DOI: https://doi.org/10.1124/jpet.102.033159
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