D-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception

Benjamin Gaston,Stephen J Lewis,James N Bates,Alex P Young,Walter J May,James M Seckler,Alan Grossfield,Santhosh M Baby,Christopher G Wilson

doi:10.1038/s41598-021-89455-2

Abstract

We have identified thiolesters that reverse the negative effects of opioids on breathing without compromising antinociception. Here we report the effects of d-cystine diethyl ester (d-cystine diEE) or d-cystine dimethyl ester (d-cystine diME) on morphine-induced changes in ventilation, arterial-blood gas chemistry, A-a gradient (index of gas-exchange in the lungs) and antinociception in freely moving rats. Injection of morphine (10 mg/kg, IV) elicited negative effects on breathing (e.g., depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive). Subsequent injection of d-cystine diEE (500 μmol/kg, IV) elicited an immediate and sustained reversal of these effects of morphine. Injection of morphine (10 mg/kg, IV) also elicited pronounced decreases in arterial blood pH, pO2 and sO2 accompanied by pronounced increases in pCO2 (all indicative of a decrease in ventilatory drive) and A-a gradient (mismatch in ventilation-perfusion in the lungs). These effects of morphine were reversed in an immediate and sustained fashion by d-cystine diME (500 μmol/kg, IV). Finally, the duration of morphine (5 and 10 mg/kg, IV) antinociception was augmented by d-cystine diEE. d-cystine diEE and d-cystine diME may be clinically useful agents that can effectively reverse the negative effects of morphine on breathing and gas-exchange in the lungs while promoting antinociception. Our study suggests that the d-cystine thiolesters are able to differentially modulate the intracellular signaling cascades that mediate morphine-induced ventilatory depression as opposed to those that mediate morphine-induced antinociception and sedation.

Highlights

We have identified thiolesters that reverse the negative effects of opioids on breathing without compromising antinociception
The injection of morphine elicited a brief increase in frequency of breathing (Freq) that was followed a relatively transient decrease that recovered before injection of vehicle of d-cystine diEE
As a result of the above changes in Freq and tidal volume (TV), it can be seen that morphine elicited a transient increase in minute ventilation (MV) that was followed by a sustained decrease and that d-cystine diEE elicited a prompt and long-lasting reversal of this effect of morphine

Summary

Introduction

We have identified thiolesters that reverse the negative effects of opioids on breathing without compromising antinociception. We report that systemic injection of d-cystine diEE or d-cystine diME elicits a rapid and sustained reversal of the negative effects of morphine on ventilatory parameters, A-a gradient and ABG chemistry whereas it augmented the analgesic actions of the opioid agonist. This pharmacological profile would be advantageous in many clinical settings involving patients who require opioids for essential pain relief (e.g., those just having undergone surgery) and who cannot be administered opioid receptor antagonists to overcome serious ventilatory depression

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Discussion

Conclusion