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

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, arte...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/41ace98fd93a40d48fca5e4e1a53a813
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:41ace98fd93a40d48fca5e4e1a53a813
record_format	dspace
spelling	oai:doaj.org-article:41ace98fd93a40d48fca5e4e1a53a8132021-12-02T15:36:31Zd-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception10.1038/s41598-021-89455-22045-2322https://doaj.org/article/41ace98fd93a40d48fca5e4e1a53a8132021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89455-2https://doaj.org/toc/2045-2322Abstract 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.Benjamin GastonSanthosh M. BabyWalter J. MayAlex P. YoungAlan GrossfieldJames N. BatesJames M. SecklerChristopher G. WilsonStephen J. LewisNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception
description	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.
format	article
author	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
author_facet	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
author_sort	Benjamin Gaston
title	d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception
title_short	d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception
title_full	d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception
title_fullStr	d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception
title_full_unstemmed	d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception
title_sort	d-cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/41ace98fd93a40d48fca5e4e1a53a813
work_keys_str_mv	AT benjamingaston dcystinedimethylesterreversesthedeleteriouseffectsofmorphineonventilationandarterialbloodgaschemistrywhilepromotingantinociception AT santhoshmbaby dcystinedimethylesterreversesthedeleteriouseffectsofmorphineonventilationandarterialbloodgaschemistrywhilepromotingantinociception AT walterjmay dcystinedimethylesterreversesthedeleteriouseffectsofmorphineonventilationandarterialbloodgaschemistrywhilepromotingantinociception AT alexpyoung dcystinedimethylesterreversesthedeleteriouseffectsofmorphineonventilationandarterialbloodgaschemistrywhilepromotingantinociception AT alangrossfield dcystinedimethylesterreversesthedeleteriouseffectsofmorphineonventilationandarterialbloodgaschemistrywhilepromotingantinociception AT jamesnbates dcystinedimethylesterreversesthedeleteriouseffectsofmorphineonventilationandarterialbloodgaschemistrywhilepromotingantinociception AT jamesmseckler dcystinedimethylesterreversesthedeleteriouseffectsofmorphineonventilationandarterialbloodgaschemistrywhilepromotingantinociception AT christophergwilson dcystinedimethylesterreversesthedeleteriouseffectsofmorphineonventilationandarterialbloodgaschemistrywhilepromotingantinociception AT stephenjlewis dcystinedimethylesterreversesthedeleteriouseffectsofmorphineonventilationandarterialbloodgaschemistrywhilepromotingantinociception
_version_	1718386285332135936

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

Ejemplares similares