{"doi":"10.3389/fphar.2022.892307","title":"S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats","abstract":") and Alveolar-arterial gradient (i.e., index of gas exchange) were markedly diminished in anesthetized Sprague Dawley rats that received a continuous intravenous infusion of the endogenous S-nitrosothiol, S-nitroso-L-cysteine. The present study extends these findings by showing that unanesthetized adult male Sprague Dawley rats receiving an intravenous infusion of S-nitroso-L-cysteine (100 or 200 nmol/kg/min) markedly diminished the ability of intravenous injections of the potent synthetic opioid, fentanyl (10, 25, and 50 μg/kg), to depress the frequency of breathing, tidal volume, and minute ventilation. Our study also found that the ability of intravenously injected fentanyl (10, 25, and 50 μg/kg) to disturb eupneic breathing, which was measured as a marked increase of the non-eupneic breathing index, was substantially reduced in unanesthetized rats receiving intravenous infusions of S-nitroso-L-cysteine (100 or 200 nmol/kg/min). In contrast, the deleterious effects of fentanyl (10, 25, and 50 μg/kg) on frequency of breathing, tidal volume, minute ventilation and non-eupneic breathing index were fully expressed in rats receiving continuous infusions (200 nmol/kg/min) of the parent amino acid, L-cysteine, or the D-isomer, namely, S-nitroso-D-cysteine. In addition, the antinociceptive actions of the above doses of fentanyl as monitored by the tail-flick latency assay, were enhanced by S-nitroso-L-cysteine, but not L-cysteine or S-nitroso-D-cysteine. Taken together, these findings add to existing knowledge that S-nitroso-L-cysteine stereoselectively modulates the detrimental effects of opioids on breathing, and opens the door for mechanistic studies designed to establish whether the pharmacological actions of S-nitroso-L-cysteine involve signaling processes that include 1) the activation of plasma membrane ion channels and receptors, 2) selective intracellular entry of S-nitroso-L-cysteine, and/or 3) S-nitrosylation events. Whether alterations in the bioavailability and bioactivity of endogenous S-nitroso-L-cysteine is a key factor in determining the potency/efficacy of fentanyl on breathing is an intriguing question.","journal":"Frontiers in Pharmacology","year":2022,"id":251906,"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":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9521,"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":712260,"name":"Ryan B. Gruber","orcid":null,"position":2,"is_corresponding":false},{"id":286633,"name":"Benjamin Gaston","orcid":"0000-0001-8794-1062","position":3,"is_corresponding":false},{"id":479497,"name":"Tristan H. Lewis","orcid":"0000-0001-9697-5045","position":4,"is_corresponding":false},{"id":587295,"name":"Alan Grossfield","orcid":"0000-0002-5877-2789","position":5,"is_corresponding":false},{"id":479496,"name":"James M. Seckler","orcid":"0000-0003-3895-7257","position":6,"is_corresponding":false},{"id":755976,"name":"Yee‐Hsee Hsieh","orcid":"0000-0002-7108-0349","position":7,"is_corresponding":false},{"id":479499,"name":"James N. Bates","orcid":"0000-0002-6898-9527","position":8,"is_corresponding":false},{"id":258278,"name":"Stephen J. Lewis","orcid":"0000-0001-7050-0666","position":9,"is_corresponding":false},{"id":425582,"name":"Paulina M. Getsy","orcid":null,"position":0,"is_corresponding":true}],"reference_count":246,"raw_metadata":null,"created_at":"2026-07-19T00:24:41.993282Z","pmid":"35721204","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":[]}