ArticleeLife2022
Endocytic trafficking determines cellular tolerance of presynaptic opioid signaling.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 27 citations in OpenAlex.
- Olfactory-gustatory cross-modal integration: mechanisms of aroma-induced sweetness enhancement, sensory evaluation methodologies, neuroimaging evidence and advances in influencing factors.Journal of advanced research · 2026Review
- Membrane lipid poly-unsaturation selectively affects dopamine D2 receptor endocytosis.Nature communications · 2026Article
- Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets.Cell · 2026Article
- Lysosomal down-regulation of the mu opioid receptor is opposed by the Retromer complex.Science advances · 2026Article
- The neural circuits and signalling pathways of opioid use disorder.Nature reviews. Neuroscience · 2025Review
- Narrative review of the scientific and methodological explanations for 101 mechanisms of opioid tolerance.Pain reports · 2025Article
- Proenkephalin 119-159 in Heart Failure: From Pathophysiology to Clinical Implications.Journal of clinical medicine · 2025Review
- Pain Signaling by GPCRs and RTKs.Trends in pharmacological sciences · 2025Review
- GPER Enhances Chronic Burn Pain via PKC-Mediated Mu-Opioid Receptor Phosphorylation in the Rostral Ventromedial Medulla.Journal of pain research · 2025Article
- Role of the G protein-coupled receptor kinase 2/3 N terminus in discriminating the endocytic effects of opioid agonist drugs.Molecular pharmacology · 2025Article
- Chronic morphine treatment induces sex- and synapse-specific cellular tolerance on thalamo-cortical mu opioid receptor signaling.Journal of neurophysiology · 2024Article
- Emerging modes of regulation of neuromodulatory G protein-coupled receptors.Trends in neurosciences · 2024Review
- Chronic Morphine Induces Adaptations in Opioid Receptor Signaling in a Thalamostriatal Circuit That Are Location Dependent, Sex Specific, and Regulated by μ-Opioid Receptor Phosphorylation.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Distinct beta-arrestin coupling and intracellular trafficking of metabotropic glutamate receptor homo- and heterodimers.Science advances · 2023Article
- Carfentanil is a β-arrestin-biased agonist at the μ opioid receptor.British journal of pharmacology · 2023Article
- Monoacylglycerol Lipase Protects the Presynaptic Cannabinoid 1 Receptor from Desensitization by Endocannabinoids after Persistent Inflammation.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Subcellular location defines GPCR signal transduction.Science advances · 2023Article
- Key differences in regulation of opioid receptors localized to presynaptic terminals compared to somas: Relevance for novel therapeutics.Neuropharmacology · 2023Review
- Chronic morphine induces adaptations in opioid receptor signaling in a thalamo-cortico-striatal circuit that are projection-dependent, sex-specific and regulated by mu opioid receptor phosphorylation.bioRxiv : the preprint server for biology · 2023Article
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Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Opioid tolerance is well-described physiologically but its mechanistic basis remains incompletely understood. An important site of opioid action in vivo is the presynaptic terminal, where opioids inhibit transmitter release. This response characteristically resists desensitization over minutes yet becomes gradually tolerant over hours, and how this is possible remains unknown. Here, we delineate a cellular mechanism underlying this longer-term form of opioid tolerance in cultured rat medium spiny neurons. Our results support a model in which presynaptic tolerance is mediated by a gradual depletion of cognate receptors from the axon surface through iterative rounds of receptor endocytosis and recycling. For the μ-opioid receptor (MOR), we show that the agonist-induced endocytic process which initiates iterative receptor cycling requires GRK2/3-mediated phosphorylation of the receptor's cytoplasmic tail, and that partial or biased agonist drugs with reduced ability to drive phosphorylation-dependent endocytosis in terminals produce correspondingly less presynaptic tolerance. We then show that the δ-opioid receptor (DOR) conforms to the same general paradigm except that presynaptic endocytosis of DOR, in contrast to MOR, does not require phosphorylation of the receptor's cytoplasmic tail. Further, we show that DOR recycles less efficiently than MOR in axons and, consistent with this, that DOR tolerance develops more strongly. Together, these results delineate a cellular basis for the development of presynaptic tolerance to opioids and describe a methodology useful for investigating presynaptic neuromodulation more broadly.
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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.