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Research ArticleNEUROPHARMACOLOGY

μ-Opioid-Induced Desensitization of Opioid Receptor-Like 1 and μ-Opioid Receptors: Differential Intracellular Signaling Determines Receptor Sensitivity

Chitra D. Mandyam, Deepak R. Thakker and Kelly M. Standifer
Journal of Pharmacology and Experimental Therapeutics September 2003, 306 (3) 965-972; DOI: https://doi.org/10.1124/jpet.103.051599
Chitra D. Mandyam
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Deepak R. Thakker
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Kelly M. Standifer
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Abstract

μ-Opioid receptors have been shown to contribute to orphanin FQ/nociceptin (OFQ/N)-mediated analgesia and hyperalgesia, indicating that both pro- and antinociceptive actions of OFQ/N are influenced by μ-opioid receptors. A 60-min activation of μ-or opioid receptor-like 1 (ORL1) opioid receptors natively expressed in BE(2)-C human neuroblastoma cells desensitized both μ- and ORL1 receptor-mediated inhibition of cAMP accumulation. The mechanism(s) of OFQ/N-mediated μ- and ORL1 cross talk involves the conventional protein kinase C isozyme, PKC-α, and G protein-coupled receptor kinases (GRKs) 2 and 3. Unlike OFQ/N-mediated desensitization of ORL1 and μ-opioid receptors, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO)-mediated ORL1 desensitization in BE(2)-C cells is PKC-independent. However, DAMGO (1 μM) pretreatment increased membrane levels of GRK2 and GRK3, indicating their translocation to the membrane upon activation. This suggests that DAMGO activation of μ-opioid receptors results in GRK2 and GRK3 inactivation of ORL1 upon challenge with OFQ/N. Antisense, but not sense, DNA selectively targeting GRK2 or GRK3 blocks DAMGO-mediated μ- and ORL1 desensitization, respectively. However, in SH-SY5Y neuroblastoma cells, DAMGO failed to desensitize ORL1 or alter membrane PKC-α or GRK levels. Instead, DAMGO stimulated PKC-ϵ translocation to the cell membrane and produced μ-receptor desensitization. These results indicate that acute exposure to μ-receptor agonists can regulate ORL1 function, but the ability to do so varies from cell type to cell type. These results also confirm the existence of multiple signaling mechanisms for μ-opioid receptors and the importance of these mechanisms for μ-receptor-mediated-heterologous effects.

Footnotes

  • ↵1 C.D.M. and D.R.T. contributed equally to this work.

  • ↵2 Present address: Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.

  • This work was supported in part upon work sponsored by U.S. Public Health Service grants from the National Institute on Drug Abuse to C.D.M. (DA14171) and K.M.S. (DA10738), as well as the Texas Advanced Research Program (003652-0114-1999 and 003652-0182-2001) and the Wendy Will Case Cancer Fund to K.M.S.

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

  • DOI: 10.1124/jpet.103.051599.

  • ABBREVIATIONS: ORL1, opioid receptor-like 1 receptor (same as the International Union of Pharmacology designated nociceptin opioid peptide receptor or NOP); OFQ/N, orphanin FQ/nociceptin; β-FNA, β-funaltrexamine; DAMGO, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; ERK, extracellular signal-regulated kinase; CHO, Chinese hamster ovary; PKC, Protein kinase C; GRK, G protein-coupled receptor kinase; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; MEK, mitogen-activated protein kinase kinase; ODN, oligodeoxynucleotide; BSA, bovine serum albumin; TBS/T, Tris-buffered saline/Tween 20; ANOVA, analysis of variance; PD98059, 4H-2-benzopyran-4-one-2-(2-amino-3-methoxy phenyl.

    • Received March 17, 2003.
    • Accepted May 12, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 306 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 3
1 Sep 2003
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Research ArticleNEUROPHARMACOLOGY

μ-Opioid-Induced Desensitization of Opioid Receptor-Like 1 and μ-Opioid Receptors: Differential Intracellular Signaling Determines Receptor Sensitivity

Chitra D. Mandyam, Deepak R. Thakker and Kelly M. Standifer
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 965-972; DOI: https://doi.org/10.1124/jpet.103.051599

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Research ArticleNEUROPHARMACOLOGY

μ-Opioid-Induced Desensitization of Opioid Receptor-Like 1 and μ-Opioid Receptors: Differential Intracellular Signaling Determines Receptor Sensitivity

Chitra D. Mandyam, Deepak R. Thakker and Kelly M. Standifer
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 965-972; DOI: https://doi.org/10.1124/jpet.103.051599
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