{"doi":"10.3390/molecules27185826","title":"Ligand-Free Signaling of G-Protein-Coupled Receptors: Relevance to μ Opioid Receptors in Analgesia and Addiction","abstract":"Numerous G-protein-coupled receptors (GPCRs) display ligand-free basal signaling with potential physiological functions, a target in drug development. As an example, the μ opioid receptor (MOR) signals in ligand-free form (MOR-μ*), influencing opioid responses. In addition, agonists bind to MOR but can dissociate upon MOR activation, with ligand-free MOR-μ* carrying out signaling. Opioid pain therapy is effective but incurs adverse effects (ADRs) and risk of opioid use disorder (OUD). Sustained opioid agonist exposure increases persistent basal MOR-μ* activity, which could be a driving force for OUD and ADRs. Antagonists competitively prevent resting MOR (MOR-μ) activation to MOR-μ*, while common antagonists, such as naloxone and naltrexone, also bind to and block ligand-free MOR-μ*, acting as potent inverse agonists. A neutral antagonist, 6β-naltrexol (6BN), binds to but does not block MOR-μ*, preventing MOR-μ activation only competitively with reduced potency. We hypothesize that 6BN gradually accelerates MOR-μ* reversal to resting-state MOR-μ. Thus, 6BN potently prevents opioid dependence in rodents, at doses well below those blocking antinociception or causing withdrawal. Acting as a 'retrograde addiction modulator', 6BN could represent a novel class of therapeutics for OUD. Further studies need to address regulation of MOR-μ* and, more broadly, the physiological and pharmacological significance of ligand-free signaling in GPCRs.","journal":"Molecules","year":2022,"id":282695,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":513715,"name":"John C. McKew","orcid":"0000-0003-0771-8114","position":1,"is_corresponding":false},{"id":378517,"name":"Wolfgang Sadée","orcid":"0000-0003-1894-6374","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-19T00:29:19.691592Z","pmid":"36144565","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":[]}