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

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

doi:10.1038/s41598-021-89455-2

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

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

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

Scientific reports, Vol.11(May (E-published)), pp.10038-10038

05/11/2021

DOI: 10.1038/s41598-021-89455-2

PMCID: PMC8113454

PMID: 33976311

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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, pO 2 and sO 2 accompanied by pronounced increases in pCO 2 (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.

Systems Biology

Drug discovery

Details

Title: Subtitle: d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception
Creators: Benjamin Gaston - Indiana University
Santhosh M. Baby - Present Address: Translational Sciences Treatment Discovery, Galvani Bioelectronics, Inc., 1250 S Collegeville Rd., Collegeville, PA 1r9426 USA
Walter J. May - Charlottesville, VA 22908 USA
Alex P. Young - Charlottesville, VA 22908 USA
Alan Grossfield - University of Rochester Medical Center
James N. Bates - University of Iowa, Anesthesia
James M. Seckler - Cleveland, OH 44106 USA
Christopher G. Wilson - Loma Linda University
Stephen J. Lewis - Case Western Reserve University
Resource Type: Journal article
Publication Details: Scientific reports, Vol.11(May (E-published)), pp.10038-10038
DOI: 10.1038/s41598-021-89455-2
PMID: 33976311
PMCID: PMC8113454
NLM abbreviation: Sci Rep
ISSN: 2045-2322
eISSN: 2045-2322
Publisher: Nature Publishing Group UK
Language: English
Date published: 05/11/2021
Academic Unit: Anesthesia
Record Identifier: 9984425351902771

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