{"doi":"10.1111/bph.15334","title":"A novel G protein‐biased agonist at the μ opioid receptor induces substantial receptor desensitisation through G protein‐coupled receptor kinase","abstract":"BACKGROUND AND PURPOSE: G protein-biased μ opioid receptor agonists have the potential to induce less receptor desensitisation and tolerance than balanced opioids. Here, we investigated if the cyclic endomorphin analogue Tyr-c[D-Lys-Phe-Tyr-Gly] (Compound 1) is a G protein-biased μ agonist and characterised its ability to induce rapid receptor desensitisation in mammalian neurones. EXPERIMENTAL APPROACH: The signalling and trafficking properties of opioids were characterised using bioluminescence resonance energy transfer assays, enzyme-linked immunosorbent assay and phosphosite-specific immunoblotting in human embryonic kidney 293 cells. Desensitisation of opioid-induced currents were studied in rat locus coeruleus neurones using whole-cell patch-clamp electrophysiology. The mechanism of Compound 1-induced μ receptor desensitisation was probed using kinase inhibitors. KEY RESULTS: Compound 1 has similar intrinsic activity for G protein signalling as morphine. As predicted for a G protein-biased μ agonist, Compound 1 induced minimal agonist-induced internalisation and phosphorylation at intracellular μ receptor serine/threonine residues known to be involved in G protein-coupled receptor kinase (GRK)-mediated desensitisation. However, Compound 1 induced robust rapid μ receptor desensitisation in locus coeruleus neurons, to a greater degree than morphine. The extent of Compound 1-induced desensitisation was unaffected by activation or inhibition of protein kinase C (PKC) but was significantly reduced by inhibition of GRK. CONCLUSION AND IMPLICATIONS: Compound 1 is a novel G protein-biased μ agonist that induces substantial rapid receptor desensitisation in mammalian neurons. Surprisingly, Compound 1-induced desensitisation was demonstrated to be GRK dependent despite its G protein bias. Our findings refute the assumption that G protein-biased agonists will evade receptor desensitisation and tolerance. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.","journal":"British Journal of Pharmacology","year":2020,"id":87147,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":443576,"name":"Nina Kathleen Blum","orcid":"0000-0002-9598-0325","position":1,"is_corresponding":false},{"id":443577,"name":"Alexandra E. Conibear","orcid":"0000-0001-5471-1375","position":2,"is_corresponding":false},{"id":407864,"name":"Alexander P. S. Disney","orcid":null,"position":3,"is_corresponding":false},{"id":443578,"name":"R. W. Hill","orcid":"0000-0003-3859-8506","position":4,"is_corresponding":false},{"id":313535,"name":"Stephen M. Husbands","orcid":"0000-0002-9928-6322","position":5,"is_corresponding":false},{"id":443579,"name":"Yangmei Li","orcid":"0000-0002-2705-3087","position":6,"is_corresponding":false},{"id":443580,"name":"Lawrence Toll","orcid":"0000-0002-4501-7573","position":7,"is_corresponding":false},{"id":443581,"name":"Andrea Kliewer","orcid":"0000-0002-1320-6505","position":8,"is_corresponding":false},{"id":443582,"name":"Stefan Schulz","orcid":"0000-0002-5997-8885","position":9,"is_corresponding":false},{"id":443583,"name":"Graeme Henderson","orcid":"0000-0001-6050-0048","position":10,"is_corresponding":false},{"id":443584,"name":"Eamonn Kelly","orcid":"0000-0002-9183-3993","position":11,"is_corresponding":false},{"id":443585,"name":"Christopher Bailey","orcid":"0000-0003-0781-8887","position":12,"is_corresponding":false},{"id":444536,"name":"Sam Groom","orcid":null,"position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-18T21:59:31.247492Z","pmid":"33245558","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}