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. 2021 Mar 26;11(1):6985.
doi: 10.1038/s41598-021-86458-x.

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

Michael W Jenkins  1   2 , Faiza Khalid  3 , Santhosh M Baby  4   5 , Walter J May  6 , Alex P Young  6 , James N Bates  7 , Feixiong Cheng  8 , James M Seckler  1 , Stephen J Lewis  9   10
Affiliations

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

Michael W Jenkins et al. Sci Rep. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Upper panel: Effects of fentanyl (75 μg/kg, IV) on tail-flick latencies in rats pretreated with vehicle (VEH; 1 ml/kg, IV) or GSHee (100 μmol/kg, IV). Lower panel: Data in the upper panel expressed as maximal possible effect (MPE, %). All data are presented as mean ± SEM. There were 9 rats in each group. The data were analyzed by repeated measures ANOVA followed by multiple comparison testing as detailed in the Methods section. *P < 0.05/6 comparisons per group, significant change from post-drug (i.e., 15, 30, 60, 120, 180 or 240 min post-fentanyl versus D15 value). †P < 0.05/6 between group comparisons, GSHee versus vehicle.
Figure 2
Figure 2
Effects of fentanyl (75 μg/kg, IV) on arterial blood pH, pO2, pCO2 and sO2 values and Alveolar-arterial (A-a) gradients in rats pretreated with vehicle (VEH; 1 ml/kg, IV) or GSHee (100 μmol/kg, IV). The data are presented as mean ± SEM. The data were analyzed by repeated measures ANOVA followed by multiple comparison testing as detailed in the Methods section. There were 9 rats in each group. *P < 0.05/5 comparisons per group, significant change from post-drug. †P < 0.05/5 between group comparisons, GSHee versus vehicle.
Figure 3
Figure 3
Effects of fentanyl (75 μg/kg, IV) on frequency of breathing (top left panel), tidal volume (top right panel), inspiratory time (middle left panel), minute ventilation (middle right panel), expiratory time (bottom left panel) and tidal volume/inspiratory time (Vt/Ti) in rats pretreated with vehicle (VEH; 1 ml/kg, IV) or GSHee (100 μmol/kg, IV). The data are presented as mean ± SEM. There were 9 rats in each group. The stippled horizontal line denotes average resting values before injection of GSHee or vehicle.
Figure 4
Figure 4
Effects of fentanyl (75 μg/kg, IV) on peak inspiratory flow (top left panel), peak expiratory flow (top right panel), end inspiratory pause (middle left panel), end expiratory pause (middle right panel), and Rejection Index (bottom left panel) in rats pretreated with vehicle (VEH; 1 ml/kg, IV) or GSHee (100 μmol/kg, IV). The data are presented as mean ± SEM. There were 9 rats in each group. The stippled horizontal line denotes average resting values before injection of GSHee or vehicle.
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