{"doi":"10.3389/fphar.2022.883329","title":"D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood–Gas Chemistry in Freely-Moving Rats","abstract":"Cell-penetrant thiol esters including the disulfides, D-cystine diethyl ester and D-cystine dimethyl ester, and the monosulfide, L-glutathione ethyl ester, prevent and/or reverse the deleterious effects of opioids, such as morphine and fentanyl, on breathing and gas exchange within the lungs of unanesthetized/unrestrained rats without diminishing the antinociceptive or sedative effects of opioids. We describe here the effects of the monosulfide thiol ester, D-cysteine ethyl ester (D-CYSee), on intravenous morphine-induced changes in ventilatory parameters, arterial blood–gas chemistry, alveolar–arterial (A-a) gradient (i.e., index of gas exchange in the lungs), and sedation and antinociception in freely-moving rats. The bolus injection of morphine (10 mg/kg, IV) elicited deleterious effects on breathing, including depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive. Subsequent injections of D-CYSee (2 × 500 μmol/kg, IV, given 15 min apart) elicited an immediate and sustained reversal of these effects of morphine. Morphine (10 mg/kg, IV) also A-a gradient, which caused a mismatch in ventilation perfusion within the lungs, and elicited pronounced changes in arterial blood–gas chemistry, including pronounced decreases in arterial blood pH, pO 2 and sO 2 , and equally pronounced increases in pCO 2 (all responses indicative of decreased ventilatory drive). These deleterious effects of morphine were immediately reversed by the injection of a single dose of D-CYSee (500 μmol/kg, IV). Importantly, the sedation and antinociception elicited by morphine (10 mg/kg, IV) were minimally affected by D-CYSee (500 μmol/kg, IV). In contrast, none of the effects of morphine were affected by administration of the parent thiol, D-cysteine (1 or 2 doses of 500 μmol/kg, IV). Taken together, these data suggest that D-CYSee may exert its beneficial effects via entry into cells that mediate the deleterious effects of opioids on breathing and gas exchange. Whether D-CYSee acts as a respiratory stimulant or counteracts the inhibitory actions of µ-opioid receptor activation remains to be determined. In conclusion, D-CYSee and related thiol esters may have clinical potential for the reversal of the adverse effects of opioids on breathing and gas exchange, while largely sparing antinociception and sedation.","journal":"Frontiers in Pharmacology","year":2022,"id":253545,"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":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.947,"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":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":286633,"name":"Benjamin Gaston","orcid":"0000-0001-8794-1062","position":4,"is_corresponding":false},{"id":364389,"name":"Matthew R. Hodges","orcid":"0000-0002-1692-9055","position":5,"is_corresponding":false},{"id":827177,"name":"H. V. Forster","orcid":"0000-0002-6228-2942","position":6,"is_corresponding":false},{"id":479499,"name":"James N. Bates","orcid":"0000-0002-6898-9527","position":7,"is_corresponding":false},{"id":834152,"name":"Christopher G. Wilson","orcid":"0000-0003-4644-5593","position":8,"is_corresponding":false},{"id":479497,"name":"Tristan H. Lewis","orcid":"0000-0001-9697-5045","position":9,"is_corresponding":false},{"id":900138,"name":"Yee-Hee Hsieh","orcid":null,"position":10,"is_corresponding":false},{"id":258278,"name":"Stephen J. Lewis","orcid":"0000-0001-7050-0666","position":11,"is_corresponding":false},{"id":425582,"name":"Paulina M. Getsy","orcid":null,"position":0,"is_corresponding":true}],"reference_count":131,"raw_metadata":null,"created_at":"2026-07-19T00:24:59.596040Z","pmid":"35814208","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":[]}