Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism

Laura Milan-Lobo, Johan Enquist, Richard M. van Rijn, Jennifer Whistler

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Delta (DOR) and mu opioid receptors (MOR) can complex as heteromers, conferring functional properties in agonist binding, signaling and trafficking that can differ markedly from their homomeric counterparts. Because of these differences, DOR/MOR heteromers may be a novel therapeutic target in the treatment of pain. However, there are currently no ligands selective for DOR/MOR heteromers, and, consequently, their role in nociception remains unknown. In this study, we used a pharmacological opioid cocktail that selectively activates and stabilizes the DOR/MOR heteromer at the cell surface by blocking its endocytosis to assess its role in antinociception. We found that mice treated chronically with this drug cocktail showed a significant right shift in the ED50 for opioid-mediated analgesia, while mice treated with a drug that promotes degradation of the heteromer did not. Furthermore, promoting degradation of the DOR/MOR heteromer after the right shift in the ED50 had occurred, or blocking signal transduction from the stabilized DOR/MOR heteromer, shifted the ED50 for analgesia back to the left. Taken together, these data suggest an anti-analgesic role for the DOR/MOR heteromer in pain. In conclusion, antagonists selective for DOR/MOR heteromer could provide an avenue for alleviating reduced analgesic response during chronic pain treatment.

Original languageEnglish (US)
Article numbere58362
JournalPLoS One
Volume8
Issue number3
DOIs
StatePublished - Mar 15 2013
Externally publishedYes

Fingerprint

delta Opioid Receptor
analgesic effect
mu Opioid Receptor
narcotics
Analgesics
Ligands
receptors
pain
Analgesia
Opioid Analgesics
analgesics
analgesia
Pain
Degradation
Signal transduction
Nociception
ligands
nociception
Endocytosis
drugs

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism. / Milan-Lobo, Laura; Enquist, Johan; van Rijn, Richard M.; Whistler, Jennifer.

In: PLoS One, Vol. 8, No. 3, e58362, 15.03.2013.

Research output: Contribution to journalArticle

Milan-Lobo, Laura ; Enquist, Johan ; van Rijn, Richard M. ; Whistler, Jennifer. / Anti-Analgesic Effect of the Mu/Delta Opioid Receptor Heteromer Revealed by Ligand-Biased Antagonism. In: PLoS One. 2013 ; Vol. 8, No. 3.
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