ArticleNature neuroscience2022
Ptchd1 mediates opioid tolerance via cholesterol-dependent effects on μ-opioid receptor trafficking.
Article in Nature neuroscience, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- G protein regulatory network shapes magnitude and kinetics of behavioral responses in an engineered opioid receptor model.The Journal of biological chemistry · 2026Article
- Advances in drug addiction research usingFrontiers in cell and developmental biology · 2026Review
- Narrative review of the scientific and methodological explanations for 101 mechanisms of opioid tolerance.Pain reports · 2025Article
- Allosteric Modulation of Cannabinoid Type 1 Receptor by ZCZ011: Integration of In Vitro Pharmacology and Molecular Dynamics Simulation.ACS bio & med chem Au · 2025Article
- UBR-1 enzyme network regulates glutamate homeostasis to affect organismal behavior and developmental viability.bioRxiv : the preprint server for biology · 2025Article
- Homeostatic scaling of dynorphin signaling by a non-canonical opioid receptor.Nature communications · 2025Article
- Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensor.Journal of lipid research · 2025Article
- Determination of the Cannabinoid CB1 Receptor's Positive Allosteric Modulator Binding Site through Mutagenesis Studies.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Mapping Astrocytic and Neuronal μ-opioid Receptor Expression in Various Brain Regions Using MOR-mCherry Reporter Mouse.Experimental neurobiology · 2023Article
- Cellular and molecular mechanisms of Hedgehog signalling.Nature reviews. Molecular cell biology · 2023Review
- Dual mechanisms of cholesterol-GPCR interactions that depend on membrane phospholipid composition.Structure (London, England : 1993) · 2023Article
- Patching holes in the mechanism of opioid tolerance.Trends in pharmacological sciences · 2023Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Repeated exposure to opioids causes tolerance, which limits their analgesic utility and contributes to overdose and abuse liability. However, the molecular mechanisms underpinning tolerance are not well understood. Here, we used a forward genetic screen in Caenorhabditis elegans for unbiased identification of genes regulating opioid tolerance which revealed a role for PTR-25/Ptchd1. We found that PTR-25/Ptchd1 controls μ-opioid receptor trafficking and that these effects were mediated by the ability of PTR-25/Ptchd1 to control membrane cholesterol content. Electrophysiological studies showed that loss of Ptchd1 in mice reduced opioid-induced desensitization of neurons in several brain regions and the peripheral nervous system. Mice and C. elegans lacking Ptchd1/PTR-25 display similarly augmented responses to opioids. Ptchd1 knockout mice fail to develop analgesic tolerance and have greatly diminished somatic withdrawal. Thus, we propose that Ptchd1 plays an evolutionarily conserved role in protecting the μ-opioid receptor against overstimulation.
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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.