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Here we report the effects of <jats:sc>d<\/jats:sc>-cystine diethyl ester (<jats:sc>d<\/jats:sc>-cystine diEE) or <jats:sc>d<\/jats:sc>-cystine dimethyl ester (<jats:sc>d<\/jats:sc>-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\u00a0mg\/kg, IV) elicited negative effects on breathing (e.g., depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive). Subsequent injection of <jats:sc>d<\/jats:sc>-cystine diEE (500\u00a0\u03bcmol\/kg, IV) elicited an immediate and sustained reversal of these effects of morphine. Injection of morphine (10\u00a0mg\/kg, IV) also elicited pronounced decreases in arterial blood pH, pO<jats:sub>2<\/jats:sub> and sO<jats:sub>2<\/jats:sub> accompanied by pronounced increases in pCO<jats:sub>2<\/jats:sub> (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 <jats:sc>d<\/jats:sc>-cystine diME (500\u00a0\u03bcmol\/kg, IV). Finally, the duration of morphine (5 and 10\u00a0mg\/kg, IV) antinociception was augmented by <jats:sc>d<\/jats:sc>-cystine diEE. <jats:sc>d<\/jats:sc>-cystine diEE and <jats:sc>d<\/jats:sc>-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 <jats:sc>d<\/jats:sc>-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.<\/jats:p>","DOI":"10.1038\/s41598-021-89455-2","type":"journal-article","created":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T10:09:20Z","timestamp":1620727760000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception"],"prefix":"10.1038","volume":"11","author":[{"given":"Benjamin","family":"Gaston","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santhosh M.","family":"Baby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter J.","family":"May","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex P.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Grossfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James N.","family":"Bates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Seckler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher G.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,11]]},"reference":[{"key":"89455_CR1","doi-asserted-by":"publisher","first-page":"e168","DOI":"10.1016\/j.bja.2018.12.023","volume":"122","author":"MH Algera","year":"2019","unstructured":"Algera, M. 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