Role of protein kinase C in functional selectivity for desensitization at the μ-opioid receptor

From pharmacological curiosity to therapeutic potential

Susan Ingram, John R. Traynor

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Opioid agonists are the best therapy for moderate to severe pain, but clinical use is limited due to the development of tolerance and dependence. For the first time, Bailey and co-workers have demonstrated functional selectivity for agonist-induced desensitization of μ-opioid receptors (MOR) in mature rat locus coeruleus neurons. Native MORs are differentially desensitized through separate, agonist-dependent signalling pathways; desensitization of the morphine-occupied receptor occurs via a protein kinase C alpha-dependent pathway while [D-Ala 2, N-MePhe 4, Gly-ol]enkephalin-mediated desensitization is via a G protein receptor kinase subtype 2-dependent mechanism. These results suggest that MORs adopt separate conformational states that either result in different efficiencies of G protein activation or access to phosphorylation by desensitization machinery (e.g. protein kinase C alpha or G protein receptor kinase subtype 2). Further study of the interaction of protein kinase C with MORs in native neurons will enhance our understanding of agonist-induced functional selectivity for desensitization at MORs and provide important insights into how to selectively modulate agonist efficacy to enhance therapeutic capabilities of opioid drugs.

Original languageEnglish (US)
Pages (from-to)154-156
Number of pages3
JournalBritish Journal of Pharmacology
Volume158
Issue number1
DOIs
StatePublished - Sep 2009
Externally publishedYes

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Exploratory Behavior
Opioid Receptors
Protein Kinase C
Pharmacology
Protein Kinase C-alpha
Cyclic GMP-Dependent Protein Kinases
glycyl-glycyl-glycyl-glycine
GTP-Binding Proteins
Opioid Analgesics
Therapeutics
Neurons
Locus Coeruleus
Enkephalins
mu Opioid Receptor
Protein Kinases
Phosphorylation
Psychologic Desensitization
Pain
Pharmaceutical Preparations

Keywords

  • μ-opioid receptor
  • DAMGO
  • Desensitization
  • G protein
  • G protein-coupled receptor kinase (GRK)
  • Morphine
  • Opiate
  • Opioid
  • PKC
  • Tolerance

ASJC Scopus subject areas

  • Pharmacology

Cite this

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abstract = "Opioid agonists are the best therapy for moderate to severe pain, but clinical use is limited due to the development of tolerance and dependence. For the first time, Bailey and co-workers have demonstrated functional selectivity for agonist-induced desensitization of μ-opioid receptors (MOR) in mature rat locus coeruleus neurons. Native MORs are differentially desensitized through separate, agonist-dependent signalling pathways; desensitization of the morphine-occupied receptor occurs via a protein kinase C alpha-dependent pathway while [D-Ala 2, N-MePhe 4, Gly-ol]enkephalin-mediated desensitization is via a G protein receptor kinase subtype 2-dependent mechanism. These results suggest that MORs adopt separate conformational states that either result in different efficiencies of G protein activation or access to phosphorylation by desensitization machinery (e.g. protein kinase C alpha or G protein receptor kinase subtype 2). Further study of the interaction of protein kinase C with MORs in native neurons will enhance our understanding of agonist-induced functional selectivity for desensitization at MORs and provide important insights into how to selectively modulate agonist efficacy to enhance therapeutic capabilities of opioid drugs.",
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