Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects

A. Kliewer, F. Schmiedel, S. Sianati, A. Bailey, J. T. Bateman, E. S. Levitt, John Williams, M. J. Christie, S. Schulz

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Opioid analgesics are powerful pain relievers; however, over time, pain control diminishes as analgesic tolerance develops. The molecular mechanisms initiating tolerance have remained unresolved to date. We have previously shown that desensitization of the μ-opioid receptor and interaction with β-arrestins is controlled by carboxyl-terminal phosphorylation. Here we created knockin mice with a series of serine- and threonine-to-alanine mutations that render the receptor increasingly unable to recruit β-arrestins. Desensitization is inhibited in locus coeruleus neurons of mutant mice. Opioid-induced analgesia is strongly enhanced and analgesic tolerance is greatly diminished. Surprisingly, respiratory depression, constipation, and opioid withdrawal signs are unchanged or exacerbated, indicating that β-arrestin recruitment does not contribute to the severity of opioid side effects and, hence, predicting that G-protein-biased µ-agonists are still likely to elicit severe adverse effects. In conclusion, our findings identify carboxyl-terminal multisite phosphorylation as key step that drives acute μ-opioid receptor desensitization and long-term tolerance.

Original languageEnglish (US)
Article number367
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

analgesia
phosphorylation
Phosphorylation
Opioid Receptors
GTP-Binding Proteins
Analgesia
Opioid Analgesics
pain
Arrestins
proteins
mice
Analgesics
alanine
loci
mutations
Arrestin
neurons
Pain
Locus Coeruleus
Threonine

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects. / Kliewer, A.; Schmiedel, F.; Sianati, S.; Bailey, A.; Bateman, J. T.; Levitt, E. S.; Williams, John; Christie, M. J.; Schulz, S.

In: Nature Communications, Vol. 10, No. 1, 367, 01.12.2019.

Research output: Contribution to journalArticle

Kliewer, A. ; Schmiedel, F. ; Sianati, S. ; Bailey, A. ; Bateman, J. T. ; Levitt, E. S. ; Williams, John ; Christie, M. J. ; Schulz, S. / Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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