l-Cysteine ethyl ester reverses the deleterious effects of morphine on, arterial blood-gas chemistry in tracheotomized rats

•l-CYSee minimally affected the negative actions of morphine on arterial blood-gas chemistry (ABG) in non-tracheotomized rats.•l-CYSee reversed the negative actions of morphine in tracheotomized rats.•l-Cysteine or l-SERee did not alter the actions of morphine on ABG in tracheotomized rats.•l-CYSee reverses morphine effects on ABG but this positive activity is negated by increases in upper-airway resistance.•Cell penetrability and the sulfur moiety drive l-CYSee activity.

This study determined whether the membrane-permeable ventilatory stimulant, l-cysteine ethylester (l-CYSee), reversed the deleterious actions of morphine on arterial blood-gas chemistry in isoflurane-anesthetized rats. Morphine (2 mg/kg, i.v.) elicited sustained decreases in arterial blood pH, pO2 and sO2, and increases in pCO2 (all responses indicative of hypoventilation) and alveolar-arterial gradient (indicative of ventilation-perfusion mismatch). Injections of l-CYSee (100 μmol/kg, i.v.) reversed the effects of morphine in tracheotomized rats but were minimally active in non-tracheotomized rats. l-cysteine or l-serine ethylester (100 μmol/kg, i.v.) were without effect. It is evident that l-CYSee can reverse the negative effects of morphine on arterial blood-gas chemistry and alveolar-arterial gradient but that this positive activity is negated by increases in upper-airway resistance. Since l-cysteine and l-serine ethylester were ineffective, it is evident that cell penetrability and the sulfur moiety of l-CYSee are essential for activity. Due to its ready penetrability into the lungs, chest wall muscle and brain, the effects of l-CYSee on morphine-induced changes in arterial blood-gas chemistry are likely to involve both central and peripheral sites of action.