L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats
We are developing a series of thiolesters that produce an immediate and sustained reversal of the deleterious effects of opioids, such as morphine and fentanyl, on ventilation without diminishing the antinociceptive effects of these opioids. We report here the effects of systemic injections of L-cys...
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.968378/full |
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| author | Paulina M. Getsy Santhosh M. Baby Walter J. May James N. Bates Christopher R. Ellis Michael G. Feasel Christopher G. Wilson Tristan H. J. Lewis Benjamin Gaston Yee-Hsee Hsieh Stephen J. Lewis Stephen J. Lewis |
| author_facet | Paulina M. Getsy Santhosh M. Baby Walter J. May James N. Bates Christopher R. Ellis Michael G. Feasel Christopher G. Wilson Tristan H. J. Lewis Benjamin Gaston Yee-Hsee Hsieh Stephen J. Lewis Stephen J. Lewis |
| author_sort | Paulina M. Getsy |
| collection | DOAJ |
| description | We are developing a series of thiolesters that produce an immediate and sustained reversal of the deleterious effects of opioids, such as morphine and fentanyl, on ventilation without diminishing the antinociceptive effects of these opioids. We report here the effects of systemic injections of L-cysteine methyl ester (L-CYSme) on morphine-induced changes in ventilatory parameters, arterial-blood gas (ABG) chemistry (pH, pCO2, pO2, sO2), Alveolar-arterial (A-a) gradient (i.e., the index of alveolar gas-exchange within the lungs), and antinociception in unanesthetized Sprague Dawley rats. The administration of morphine (10 mg/kg, IV) produced a series of deleterious effects on ventilatory parameters, including sustained decreases in tidal volume, minute ventilation, inspiratory drive and peak inspiratory flow that were accompanied by a sustained increase in end inspiratory pause. A single injection of L-CYSme (500 μmol/kg, IV) produced a rapid and long-lasting reversal of the deleterious effects of morphine on ventilatory parameters, and a second injection of L-CYSme (500 μmol/kg, IV) elicited pronounced increases in ventilatory parameters, such as minute ventilation, to values well above pre-morphine levels. L-CYSme (250 or 500 μmol/kg, IV) also produced an immediate and sustained reversal of the deleterious effects of morphine (10 mg/kg, IV) on arterial blood pH, pCO2, pO2, sO2 and A-a gradient, whereas L-cysteine (500 μmol/kg, IV) itself was inactive. L-CYSme (500 μmol/kg, IV) did not appear to modulate the sedative effects of morphine as measured by righting reflex times, but did diminish the duration, however, not the magnitude of the antinociceptive actions of morphine (5 or 10 mg/kg, IV) as determined in tail-flick latency and hindpaw-withdrawal latency assays. These findings provide evidence that L-CYSme can powerfully overcome the deleterious effects of morphine on breathing and gas-exchange in Sprague Dawley rats while not affecting the sedative or early stage antinociceptive effects of the opioid. The mechanisms by which L-CYSme interferes with the OR-induced signaling pathways that mediate the deleterious effects of morphine on ventilatory performance, and by which L-CYSme diminishes the late stage antinociceptive action of morphine remain to be determined. |
| first_indexed | 2024-04-12T04:17:43Z |
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| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T04:17:43Z |
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| spelling | doaj.art-58575678264d4a8ca9cc27c71351a7452022-12-22T03:48:21ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-09-011310.3389/fphar.2022.968378968378L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized ratsPaulina M. Getsy0Santhosh M. Baby1Walter J. May2James N. Bates3Christopher R. Ellis4Michael G. Feasel5Christopher G. Wilson6Tristan H. J. Lewis7Benjamin Gaston8Yee-Hsee Hsieh9Stephen J. Lewis10Stephen J. Lewis11Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United StatesGalleon Pharmaceuticals, Inc., Horsham, PA, United StatesPediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA, United StatesDepartment of Anesthesiology, University of Iowa Hospitals and Clinics, Iowa City, IA, United StatesUnited States Army CCDC Chemical Biological Center, Aberdeen Proving Ground, MD, United StatesUnited States Army CCDC Chemical Biological Center, Aberdeen Proving Ground, MD, United StatesDepartment of Basic Sciences, Division of Physiology, School of Medicine, Loma Linda University, Loma Linda, CA, United StatesDepartment of Pediatrics, Case Western Reserve University, Cleveland, OH, United StatesHerman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United StatesDivision of Pulmonary, Critical Care and Sleep Medicine, 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 StatesWe are developing a series of thiolesters that produce an immediate and sustained reversal of the deleterious effects of opioids, such as morphine and fentanyl, on ventilation without diminishing the antinociceptive effects of these opioids. We report here the effects of systemic injections of L-cysteine methyl ester (L-CYSme) on morphine-induced changes in ventilatory parameters, arterial-blood gas (ABG) chemistry (pH, pCO2, pO2, sO2), Alveolar-arterial (A-a) gradient (i.e., the index of alveolar gas-exchange within the lungs), and antinociception in unanesthetized Sprague Dawley rats. The administration of morphine (10 mg/kg, IV) produced a series of deleterious effects on ventilatory parameters, including sustained decreases in tidal volume, minute ventilation, inspiratory drive and peak inspiratory flow that were accompanied by a sustained increase in end inspiratory pause. A single injection of L-CYSme (500 μmol/kg, IV) produced a rapid and long-lasting reversal of the deleterious effects of morphine on ventilatory parameters, and a second injection of L-CYSme (500 μmol/kg, IV) elicited pronounced increases in ventilatory parameters, such as minute ventilation, to values well above pre-morphine levels. L-CYSme (250 or 500 μmol/kg, IV) also produced an immediate and sustained reversal of the deleterious effects of morphine (10 mg/kg, IV) on arterial blood pH, pCO2, pO2, sO2 and A-a gradient, whereas L-cysteine (500 μmol/kg, IV) itself was inactive. L-CYSme (500 μmol/kg, IV) did not appear to modulate the sedative effects of morphine as measured by righting reflex times, but did diminish the duration, however, not the magnitude of the antinociceptive actions of morphine (5 or 10 mg/kg, IV) as determined in tail-flick latency and hindpaw-withdrawal latency assays. These findings provide evidence that L-CYSme can powerfully overcome the deleterious effects of morphine on breathing and gas-exchange in Sprague Dawley rats while not affecting the sedative or early stage antinociceptive effects of the opioid. The mechanisms by which L-CYSme interferes with the OR-induced signaling pathways that mediate the deleterious effects of morphine on ventilatory performance, and by which L-CYSme diminishes the late stage antinociceptive action of morphine remain to be determined.https://www.frontiersin.org/articles/10.3389/fphar.2022.968378/fullL-cysteine methylestermorphineventilatory depressionarterial blood-gas chemistrySprague Dawley rats |
| spellingShingle | Paulina M. Getsy Santhosh M. Baby Walter J. May James N. Bates Christopher R. Ellis Michael G. Feasel Christopher G. Wilson Tristan H. J. Lewis Benjamin Gaston Yee-Hsee Hsieh Stephen J. Lewis Stephen J. Lewis L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats Frontiers in Pharmacology L-cysteine methylester morphine ventilatory depression arterial blood-gas chemistry Sprague Dawley rats |
| title | L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats |
| title_full | L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats |
| title_fullStr | L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats |
| title_full_unstemmed | L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats |
| title_short | L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats |
| title_sort | l cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood gas chemistry in unanesthetized rats |
| topic | L-cysteine methylester morphine ventilatory depression arterial blood-gas chemistry Sprague Dawley rats |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.968378/full |
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