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Orphanin FQ/nociceptin-mediated desensitization of opioid receptor-like 1 receptor and mu opioid receptors involves protein kinase C: A molecular mechanism for heterologous cross-talk

Academic Article
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Overview

authors

  • Mandyam, Chitra
  • Thakker, D. R.
  • Christensen, J. L.
  • Standifer, K. M.

publication date

  • August 2002

journal

  • Journal of Pharmacology and Experimental Therapeutics  Journal

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 mu and ORL1 receptor-mediated inhibition of cAMP. Investigating the mechanism(s) of OFQ/N-mediated mu and ORL1 receptor cross-talk, we found that pretreatment with the protein kinase C inhibitor, chelerythrine chloride (1 microM), blocked OFQ/N-mediated homologous desensitization of ORL1 and heterologous desensitization of mu opioid receptors. Furthermore, depletion of PKC by 12-O-tetradecanoylphorbol-13-acetate exposure (48 h, 1 microM) also prevented OFQ/N-mediated mu and ORL1 desensitization. OFQ/N pretreatment resulted in translocation of PKC-alpha, 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 mu receptor desensitization. This suggests that PKC-alpha is required for GRK2 and GRK3 translocation to the membrane, where GRK can inactivate ORL1 and mu 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 mu-ORL1 cross-talk, and represent a possible mechanism for OFQ/N-induced anti-opioid actions.

subject areas

  • Alkaloids
  • Benzophenanthridines
  • Cell Membrane
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enzyme Inhibitors
  • G-Protein-Coupled Receptor Kinase 3
  • Humans
  • Neuroblastoma
  • Oligodeoxyribonucleotides, Antisense
  • Opioid Peptides
  • Phenanthridines
  • Protein Kinase C
  • Protein Serine-Threonine Kinases
  • Receptor Cross-Talk
  • Receptors, Opioid
  • Receptors, Opioid, mu
  • Tetradecanoylphorbol Acetate
  • Tumor Cells, Cultured
  • beta-Adrenergic Receptor Kinases
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Identity

International Standard Serial Number (ISSN)

  • 0022-3565

Digital Object Identifier (DOI)

  • 10.1124/jpet.102.033159

PubMed ID

  • 12130708
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Additional Document Info

start page

  • 502

end page

  • 509

volume

  • 302

issue

  • 2

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