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Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia
Journal article   Open access   Peer reviewed

Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia

Michael W. Jenkins, Faiza Khalid, Santhosh M. Baby, Walter J. May, Alex P. Young, James N. Bates, Feixiong Cheng, James M. Seckler and Stephen J. Lewis
Scientific reports, Vol.11(1), pp.6985-6985
03/26/2021
DOI: 10.1038/s41598-021-86458-x
PMCID: PMC7997982
PMID: 33772077
url
https://doi.org/10.1038/s41598-021-86458-xView
Published (Version of record) Open Access

Abstract

There is an urgent need to develop novel compounds that prevent the deleterious effects of opioids such as fentanyl on minute ventilation while, if possible, preserving the analgesic actions of the opioids. We report that L-glutathione ethyl ester (GSHee) may be such a novel compound. In this study, we measured tail flick latency (TFL), arterial blood gas (ABG) chemistry, Alveolar-arterial gradient, and ventilatory parameters by whole body plethysmography to determine the responses elicited by bolus injections of fentanyl (75 mu g/kg, IV) in male adult Sprague-Dawley rats that had received a bolus injection of GSHee (100 mu mol/kg, IV) 15 min previously. GSHee given alone had minimal effects on TFL, ABG chemistry and A-a gradient whereas it elicited changes in some ventilatory parameters such as an increase in breathing frequency. In vehicle-treated rats, fentanyl elicited (1) an increase in TFL, (2) decreases in pH, pO(2) and sO(2) and increases in pCO(2) (all indicative of ventilatory depression), (3) an increase in Alveolar-arterial gradient (indicative of a mismatch in ventilation-perfusion in the lungs), and (4) changes in ventilatory parameters such as a reduction in tidal volume, that were indicative of pronounced ventilatory depression. In GSHee-pretreated rats, fentanyl elicited a more prolonged analgesia, relatively minor changes in ABG chemistry and Alveolar-arterial gradient, and a substantially milder depression of ventilation. GSHee may represent an effective member of a novel class of thiolester drugs that are able to prevent the ventilatory depressant effects elicited by powerful opioids such as fentanyl and their deleterious effects on gas-exchange in the lungs without compromising opioid analgesia.
 Multidisciplinary Sciences Science & Technology Science & Technology - Other Topics

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