S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats
Endogenous and exogenously administered S-nitrosothiols modulate the activities of central and peripheral systems that control breathing. We have unpublished data showing that the deleterious effects of morphine on arterial blood-gas chemistry (i.e., pH, pCO2, pO2, and sO2) and Alveolar-arterial gra...
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| Format: | Article |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.892307/full |
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| author | Paulina M. Getsy Santhosh M. Baby Ryan B. Gruber Benjamin Gaston Tristan H. J. Lewis Alan Grossfield James M. Seckler Yee-Hsee Hsieh James N. Bates Stephen J. Lewis Stephen J. Lewis Stephen J. Lewis |
| author_facet | Paulina M. Getsy Santhosh M. Baby Ryan B. Gruber Benjamin Gaston Tristan H. J. Lewis Alan Grossfield James M. Seckler Yee-Hsee Hsieh James N. Bates Stephen J. Lewis Stephen J. Lewis Stephen J. Lewis |
| author_sort | Paulina M. Getsy |
| collection | DOAJ |
| description | Endogenous and exogenously administered S-nitrosothiols modulate the activities of central and peripheral systems that control breathing. We have unpublished data showing that the deleterious effects of morphine on arterial blood-gas chemistry (i.e., pH, pCO2, pO2, and sO2) and Alveolar-arterial gradient (i.e.,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. |
| first_indexed | 2024-12-12T05:02:01Z |
| format | Article |
| id | doaj.art-917a88664b534ff3bbaeda91c4bb6f4b |
| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-12-12T05:02:01Z |
| publishDate | 2022-05-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-917a88664b534ff3bbaeda91c4bb6f4b2022-12-22T00:37:12ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-05-011310.3389/fphar.2022.892307892307S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving RatsPaulina M. Getsy0Santhosh M. Baby1Ryan B. Gruber2Benjamin Gaston3Tristan H. J. Lewis4Alan Grossfield5James M. Seckler6Yee-Hsee Hsieh7James N. Bates8Stephen J. Lewis9Stephen J. Lewis10Stephen J. Lewis11Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United StatesGalleon Pharmaceuticals, Inc., Horsham, PA, United StatesGalleon Pharmaceuticals, Inc., Horsham, PA, United StatesHerman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Pediatrics, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United StatesDivision of Pulmonary, Critical Care and Sleep Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Anesthesia, University of Iowa, Iowa City, IA, United StatesDepartment of Pediatrics, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pharmacology, Case Western Reserve University, Cleveland, OH, United StatesFunctional Electrical Stimulation Center, Case Western Reserve University, Cleveland, OH, United StatesEndogenous and exogenously administered S-nitrosothiols modulate the activities of central and peripheral systems that control breathing. We have unpublished data showing that the deleterious effects of morphine on arterial blood-gas chemistry (i.e., pH, pCO2, pO2, and sO2) 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.https://www.frontiersin.org/articles/10.3389/fphar.2022.892307/fullS-nitrosothiolfentanylfrequency of breathingtidal volumeminute ventilationnoneupneic breathing index |
| spellingShingle | Paulina M. Getsy Santhosh M. Baby Ryan B. Gruber Benjamin Gaston Tristan H. J. Lewis Alan Grossfield James M. Seckler Yee-Hsee Hsieh James N. Bates Stephen J. Lewis Stephen J. Lewis Stephen J. Lewis S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats Frontiers in Pharmacology S-nitrosothiol fentanyl frequency of breathing tidal volume minute ventilation noneupneic breathing index |
| title | S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats |
| title_full | S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats |
| title_fullStr | S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats |
| title_full_unstemmed | S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats |
| title_short | S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats |
| title_sort | s nitroso l cysteine stereoselectively blunts the deleterious effects of fentanyl on breathing while augmenting antinociception in freely moving rats |
| topic | S-nitrosothiol fentanyl frequency of breathing tidal volume minute ventilation noneupneic breathing index |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.892307/full |
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