ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2021
Pharmacological and genetic manipulations at the µ-opioid receptor reveal arrestin-3 engagement limits analgesic tolerance and does not exacerbate respiratory depression in mice.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 60 citations in OpenAlex.
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- Internet Sales of "Research Grade Compounds": The Opioid SR-17018 (SR-17) as an Example.Cureus · 2026Review
- Knowledge graph and emerging trends in β-arrestin research on pain: a bibliometric analysis (1997-2025).Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Quantum Chemical Exploration of Fentanyl and Its Analogs: Conformational Landscapes and Energetics in Solution.ACS omega · 2025Article
- Article
- Probiotic supplementation mitigates sex-dependent nociceptive changes and gut dysbiosis induced by prenatal opioid exposure.Gut microbes · 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
- Total synthesis and biological activity of "carbamorphine": O-to-CHProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Biased Opioid Receptor Agonists: Balancing Analgesic Efficacy and Side-Effect Profiles.International journal of molecular sciences · 2025Review
- Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic morphine.bioRxiv : the preprint server for biology · 2024Article
- Nucleus accumbens sub-regions experience distinct dopamine release responses following acute and chronic morphine exposure.bioRxiv : the preprint server for biology · 2024Article
- In Vitro Functional Profiling of Fentanyl and Nitazene Analogs at the μ-Opioid Receptor Reveals High Efficacy for Gi Protein Signaling.ACS chemical neuroscience · 2024Article
- A Balancing Act: Learning from the Past to Build a Future-Focused Opioid Strategy.Annual review of physiology · 2024Review
- Deletion of arrestin-3 does not reduce drug-seeking behavior in a longitudinal paradigm of oral morphine self-administration.Frontiers in pharmacology · 2024Article
- Assessment of the potential of novel and classical opioids to induce respiratory depression in mice.British journal of pharmacology · 2023Article
- IUPHAR themed review: Opioid efficacy, bias, and selectivity.Pharmacological research · 2023Review
- Review
- Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine DJournal of medicinal chemistry · 2023Article
- Modulating GPCR and 14-3-3 protein interactions: Prospects for CNS drug discovery.Drug discovery today · 2023Review
- Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Opioid drugs are widely used analgesics that activate the G protein-coupled µ-opioid receptor, whose endogenous neuropeptide agonists, endorphins and enkephalins, are potent pain relievers. The therapeutic utility of opioid drugs is hindered by development of tolerance to the analgesic effects, requiring dose escalation for persistent pain control and leading to overdose and fatal respiratory distress. The prevailing hypothesis is that the intended analgesic effects of opioid drugs are mediated by µ-opioid receptor signaling to G protein, while the side-effects of respiratory depression and analgesic tolerance are caused by engagement of the receptor with the arrestin-3 protein. Consequently, opioid drug development has focused exclusively on identifying agonists devoid of arrestin-3 engagement. Here, we challenge the prevailing hypothesis with a panel of six clinically relevant opioid drugs and mice of three distinct genotypes with varying abilities to promote morphine-mediated arrestin-3 engagement. With this genetic and pharmacological approach, we demonstrate that arrestin-3 recruitment does not impact respiratory depression, and effective arrestin-3 engagement reduces, rather than exacerbates, the development of analgesic tolerance. These studies suggest that future development of safer opioids should focus on identifying opioid ligands that recruit both G protein and arrestin-3, thereby mimicking the signaling profile of most endogenous µ-opioid receptor agonists.
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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.