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

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 μg/kg, IV) in male adult Sprague–Dawley rats that had received a bolus injection of GSHee (100 μmol/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, pO2 and sO2 and increases in pCO2 (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.

S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats

“…Consistent with previous reports ( Jenkins et al, 2021 ; Seckler et al, 2022 ), each injection of fentanyl in vehicle-infused rats elicited substantial, relatively short-lived increases in occurrence of non-eupneic breaths, as demonstrated by the increases in NEBI and NEBI/f R . Based on the known effects of opioids on breathing patterns ( Zutler and Holty, 2011 ; Nagappa et al, 2017 ), it is likely that most non-eupneic breathing consists of breath-holds (apneas) although other events, such as type 1 and type 2 sighs, may have occurred.…”

“…Antinociception status in unanesthetized rats was determined by a radiant heat tail-flick latency (TFL) assay, as detailed previously ( Lewis et al, 1991 ; Henderson et al, 2014 ; Gaston et al, 2021 ; Jenkins et al, 2021 ). Prior to administration of fentanyl, the rats were allowed to crawl inside a canvas garden glove and lightly restrained within the glove to allow for the thermal withdrawal latencies to be determined.…”

“…All data are presented as mean ± SEM and were evaluated using one-way and two-way ANOVA followed by Bonferroni corrections for multiple comparisons between means using the error mean square terms from each ANOVA analysis ( Winer, 1971 ; Wallenstein et al, 1980 ; Ludbrook, 1998 ; McHugh, 2011 ) as detailed previously ( Getsy et al, 2021 ; Jenkins et al, 2021 ). A value of p < 0.05 was taken as the initial level of statistical significance ( Wallenstein et al, 1980 ; Ludbrook, 1998 ; McHugh, 2011 ).…”

Tempol Reverses the Negative Effects of Morphine on Arterial Blood-Gas Chemistry and Tissue Oxygen Saturation in Freely-Moving Rats

“…We recently reported that l -cysteine ethyl ester ( Mendoza et al, 2013 ), glutathione ethyl ester ( Jenkins et al, 2021 ), and d -cystine methyl and ethyl esters ( Gaston et al, 2021 ) rapidly reverse the negative effects of opioids, such as morphine and fentanyl, on breathing, Alveolar-arterial gradient (i.e., the index of gas exchange within the lungs) and arterial blood-gas (ABG) chemistry while not reducing opioid analgesia. Since these reduced and oxidized thiol esters block the negative effects of opioids on breathing and because the potent reducing agent N-acetyl- l -cysteine methyl ester does not affect opioid-induced depression of breathing ( Baby et al, 2021 , it is unlikely that the thiol esters exert their effects by altering the redox state of cells involved in the effects of opioids on breathing.…”

Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity

“…In a third study, in awake rats, the investigators show that pretreatment with glutathione ethyl ester offsets fentanyl-induced respiratory depression through effects on respiratory rate and tidal volume, and consequently stabilized breathing and enhanced analgesia. 51 In summary, these studies show that ethyl esters increase respiratory rate and sometimes also tidal volume, and that the increase is sustained during moderate opioid-induced respiratory depression, offsetting the opioid effect on respiratory rate. Finally, in awake and isoflurane-anesthetized rats, pretreatment with the antioxidant Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) prevented fentanyl-induced respiratory depression, while the potent antioxidant N-acetyl-L-cysteine methyl ester was without effect.…”