D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood–Gas Chemistry in Freely-Moving Rats
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 unan...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-06-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.883329/full |
| _version_ | 1818256254116560896 |
|---|---|
| author | Paulina M. Getsy Santhosh M. Baby Walter J. May Alex P. Young Benjamin Gaston Matthew R. Hodges Hubert V. Forster James N. Bates Christopher G. Wilson Tristan H. J. Lewis Yee-Hee Hsieh Stephen J. Lewis Stephen J. Lewis |
| author_facet | Paulina M. Getsy Santhosh M. Baby Walter J. May Alex P. Young Benjamin Gaston Matthew R. Hodges Hubert V. Forster James N. Bates Christopher G. Wilson Tristan H. J. Lewis Yee-Hee Hsieh Stephen J. Lewis Stephen J. Lewis |
| author_sort | Paulina M. Getsy |
| collection | DOAJ |
| description | 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, pO2 and sO2, and equally pronounced increases in pCO2 (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. |
| first_indexed | 2024-12-12T17:24:50Z |
| format | Article |
| id | doaj.art-498c8bb8e48f4686a17a66cbccf872fb |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-12T17:24:50Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-498c8bb8e48f4686a17a66cbccf872fb2022-12-22T00:17:34ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-06-011310.3389/fphar.2022.883329883329D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood–Gas Chemistry in Freely-Moving RatsPaulina M. Getsy0Santhosh M. Baby1Walter J. May2Alex P. Young3Benjamin Gaston4Matthew R. Hodges5Hubert V. Forster6James N. Bates7Christopher G. Wilson8Tristan H. J. Lewis9Yee-Hee Hsieh10Stephen J. Lewis11Stephen J. Lewis12Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Drug Discovery, Galleon Pharmaceuticals, Inc., Horsham, PA, United StatesPediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA, United StatesPediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA, United StatesHerman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Physiology, Medical College of Wisconsin, Milwaukee, WI, United StatesDepartment of Physiology, Medical College of Wisconsin, Milwaukee, WI, United StatesDepartment of Anesthesia, University of Iowa Hospitals and Clinics, Iowa City, IA, United StatesBasic Sciences, Division of Physiology, School of Medicine, Loma Linda University, Loma Linda, CA, United StatesDepartment of Pediatrics, Case Western Reserve University, Cleveland, OH, United StatesDivision of Pulmonary, Critical Care and Sleep Medicine, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pediatrics, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pharmacology, Case Western Reserve University, Cleveland, OH, United StatesCell-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, pO2 and sO2, and equally pronounced increases in pCO2 (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.https://www.frontiersin.org/articles/10.3389/fphar.2022.883329/fullD-cysteine ethyl esterthiol estersmorphinerespiratory depressiongas exchangeantinociception |
| spellingShingle | Paulina M. Getsy Santhosh M. Baby Walter J. May Alex P. Young Benjamin Gaston Matthew R. Hodges Hubert V. Forster James N. Bates Christopher G. Wilson Tristan H. J. Lewis Yee-Hee Hsieh Stephen J. Lewis Stephen J. Lewis D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood–Gas Chemistry in Freely-Moving Rats Frontiers in Pharmacology D-cysteine ethyl ester thiol esters morphine respiratory depression gas exchange antinociception |
| title | D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood–Gas Chemistry in Freely-Moving Rats |
| title_full | D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood–Gas Chemistry in Freely-Moving Rats |
| title_fullStr | D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood–Gas Chemistry in Freely-Moving Rats |
| title_full_unstemmed | D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood–Gas Chemistry in Freely-Moving Rats |
| title_short | D-Cysteine Ethyl Ester Reverses the Deleterious Effects of Morphine on Breathing and Arterial Blood–Gas Chemistry in Freely-Moving Rats |
| title_sort | d cysteine ethyl ester reverses the deleterious effects of morphine on breathing and arterial blood gas chemistry in freely moving rats |
| topic | D-cysteine ethyl ester thiol esters morphine respiratory depression gas exchange antinociception |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.883329/full |
| work_keys_str_mv | AT paulinamgetsy dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats AT santhoshmbaby dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats AT walterjmay dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats AT alexpyoung dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats AT benjamingaston dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats AT matthewrhodges dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats AT hubertvforster dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats AT jamesnbates dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats AT christophergwilson dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats AT tristanhjlewis dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats AT yeeheehsieh dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats AT stephenjlewis dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats AT stephenjlewis dcysteineethylesterreversesthedeleteriouseffectsofmorphineonbreathingandarterialbloodgaschemistryinfreelymovingrats |