d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception
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, arte...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-89455-2 |
| _version_ | 1819042047854641152 |
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| author | Benjamin Gaston Santhosh M. Baby Walter J. May Alex P. Young Alan Grossfield James N. Bates James M. Seckler Christopher G. Wilson Stephen J. Lewis |
| author_facet | Benjamin Gaston Santhosh M. Baby Walter J. May Alex P. Young Alan Grossfield James N. Bates James M. Seckler Christopher G. Wilson Stephen J. Lewis |
| author_sort | Benjamin Gaston |
| collection | DOAJ |
| description | 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, pO2 and sO2 accompanied by pronounced increases in pCO2 (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. |
| first_indexed | 2024-12-21T09:34:41Z |
| format | Article |
| id | doaj.art-41ace98fd93a40d48fca5e4e1a53a813 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-21T09:34:41Z |
| publishDate | 2021-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-41ace98fd93a40d48fca5e4e1a53a8132022-12-21T19:08:39ZengNature PortfolioScientific Reports2045-23222021-05-0111111410.1038/s41598-021-89455-2d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociceptionBenjamin Gaston0Santhosh M. Baby1Walter J. May2Alex P. Young3Alan Grossfield4James N. Bates5James M. Seckler6Christopher G. Wilson7Stephen J. Lewis8Herman B Wells Center for Pediatric Research, Indiana University School of MedicineTranslational Sciences Treatment Discovery, Galvani Bioelectronics, Inc.Pediatric Respiratory Medicine, University of Virginia School of MedicinePediatric Respiratory Medicine, University of Virginia School of MedicineDepartment of Biochemistry and Biophysics, University of Rochester Medical CenterDepartment of Anesthesia, University of Iowa Hospitals and ClinicsDepartment of Biomedical Engineering, Case Western Reserve UniversityBasic Sciences, Division of Physiology, School of Medicine, Loma Linda UniversityDepartment of Pharmacology, Case Western Reserve UniversityAbstract 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, pO2 and sO2 accompanied by pronounced increases in pCO2 (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.https://doi.org/10.1038/s41598-021-89455-2 |
| spellingShingle | Benjamin Gaston Santhosh M. Baby Walter J. May Alex P. Young Alan Grossfield James N. Bates James M. Seckler Christopher G. Wilson Stephen J. Lewis d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception Scientific Reports |
| title | d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception |
| title_full | d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception |
| title_fullStr | d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception |
| title_full_unstemmed | d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception |
| title_short | d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception |
| title_sort | d cystine di m ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception |
| url | https://doi.org/10.1038/s41598-021-89455-2 |
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