ArticleNature communications2019
Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects.
Article in Nature communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 173 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
173 citing papers in PubMed, 288 citations in OpenAlex.
- Tegileridine, a Biased μ-Opioid Receptor Agonist, versus Oxycodone for Postoperative Analgesia and Postoperative Nausea and Vomiting After Total Laparoscopic Hysterectomy: A Randomized, Double-Blind, Single-Center, Controlled Trial.Drug design, development and therapy · 2026Trial
- Estimation of EDDrug design, development and therapy · 2025Trial
- Internet Sales of "Research Grade Compounds": The Opioid SR-17018 (SR-17) as an Example.Cureus · 2026Review
- Arrestins as programmable integrators of GPCR signaling: structural microstates, spatiotemporal logic, and therapeutic control.Cell discovery · 2026Review
- Article
- G-protein regulatory network governs receptor internalization dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Structural dynamics of kappa opioid receptor interactions with β-arrestin 1.Nature communications · 2026Article
- Lysosomal down-regulation of the mu opioid receptor is opposed by the Retromer complex.Science advances · 2026Article
- Opioid-specific brain connectivity dynamics distinguish analgesia from secondary effects: Studies in male mice.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Knowledge graph and emerging trends in β-arrestin research on pain: a bibliometric analysis (1997-2025).Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Histamine HPharmaceuticals (Basel, Switzerland) · 2026Article
- Cell-based and isoform-selective G protein-coupled receptor kinase assays for comprehensive inhibitor evaluation.Communications biology · 2026Article
- Evaluation of AT121 versus morphine on cortical neurons electrophysiology and dopamine concentrations in hippocampal cells.PloS one · 2026Article
- Autonomic nervous system modulation by G protein-biased mu-opioid receptor agonists: A translational scoping review protocol.PloS one · 2026Article
- Elucidating biased signaling in class A GPCRs.Trends in pharmacological sciences · 2025Review
- Mitragynine and 7-hydroxymitragynine: Bidirectional effects on breathing in rats.The Journal of pharmacology and experimental therapeutics · 2025Article
- Role of β-Arrestin 2 in the antinociceptive and side effect profile of morphine and the novel mu opioid receptor agonists, kurkinorin and kurkinol.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Neuropeptides as transmitters and regulators of the locus coeruleus noradrenergic system.Pharmacological reviews · 2025Review
- Expanding Horizons of Buprenorphine: A Comprehensive Narrative Review of Its Pharmacological Properties and Clinical Applications in Chronic Pain.Pain and therapy · 2025Review
- Rational Design Biased Compounds against μ‑Opioid Receptor.ACS pharmacology & translational science · 2025Article
113 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 5 institutions in 4 countries.
Funding
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.