{"doi":"10.1038/s41598-021-89455-2","title":"d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception","abstract":"Abstract We have identified thiolesters that reverse the negative effects of opioids on breathing without compromising antinociception. Here we report the effects of d -cystine diethyl ester ( d -cystine diEE) or d -cystine dimethyl ester ( d -cystine diME) on morphine-induced changes in ventilation, arterial-blood gas chemistry, A-a gradient (index of gas-exchange in the lungs) and antinociception in freely moving rats. Injection of morphine (10 mg/kg, IV) elicited negative effects on breathing (e.g., depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive). Subsequent injection of d -cystine diEE (500 μmol/kg, IV) elicited an immediate and sustained reversal of these effects of morphine. Injection of morphine (10 mg/kg, IV) also elicited pronounced decreases in arterial blood pH, pO 2 and sO 2 accompanied by pronounced increases in pCO 2 (all indicative of a decrease in ventilatory drive) and A-a gradient (mismatch in ventilation-perfusion in the lungs). These effects of morphine were reversed in an immediate and sustained fashion by d -cystine diME (500 μmol/kg, IV). Finally, the duration of morphine (5 and 10 mg/kg, IV) antinociception was augmented by d -cystine diEE. d -cystine diEE and d -cystine diME may be clinically useful agents that can effectively reverse the negative effects of morphine on breathing and gas-exchange in the lungs while promoting antinociception. Our study suggests that the d -cystine thiolesters are able to differentially modulate the intracellular signaling cascades that mediate morphine-induced ventilatory depression as opposed to those that mediate morphine-induced antinociception and sedation.","journal":"Scientific Reports","year":2021,"id":169309,"datarank":0.5101796072493234,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"self_citation_contribution":0.5101796072493234,"citation_network_contribution":0.0,"self_endowment_contribution":0.5101796072493234,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.951,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":699748,"name":"Santhosh M. Baby","orcid":"0000-0003-4891-9924","position":1,"is_corresponding":false},{"id":700166,"name":"Walter J. May","orcid":null,"position":2,"is_corresponding":false},{"id":700167,"name":"Alex P. Young","orcid":null,"position":3,"is_corresponding":false},{"id":587295,"name":"Alan Grossfield","orcid":"0000-0002-5877-2789","position":4,"is_corresponding":false},{"id":479499,"name":"James N. Bates","orcid":"0000-0002-6898-9527","position":5,"is_corresponding":false},{"id":479496,"name":"James M. Seckler","orcid":"0000-0003-3895-7257","position":6,"is_corresponding":false},{"id":447594,"name":"Christopher G. Wilson","orcid":"0000-0001-9762-0481","position":7,"is_corresponding":false},{"id":258278,"name":"Stephen J. Lewis","orcid":"0000-0001-7050-0666","position":8,"is_corresponding":false},{"id":286633,"name":"Benjamin Gaston","orcid":"0000-0001-8794-1062","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:46:11.334362Z","pmid":"33976311","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":[]}