L-cysteine ethylester reverses the adverse effects of morphine on breathing and arterial blood-gas chemistry while minimally affecting antinociception in unanesthetized rats

L-cysteine ethylester (L-CYSee) is a membrane -permeable analogue of L-cysteine with a variety of pharmacological effects. The purpose of this study was to determine the effects of L-CYSee on morphine -induced changes in ventilation, arterial -blood gas (ABG) chemistry, Alveolar -arterial (A -a) gradient (i.e., a measure of the index of alveolar gas -exchange), antinociception and sedation in male Sprague Dawley rats. An injection of morphine (10 mg/kg, IV) produced adverse effects on breathing, including sustained decreases in minute ventilation. L-CYSee (500 mu mol/kg, IV) given 15 min later immediately reversed the actions of morphine. Another injection of LCYSee (500 mu mol/kg, IV) after 15 min elicited more pronounced excitatory ventilatory responses. L-CYSee (250 or 500 mu mol/kg, IV) elicited a rapid and prolonged reversal of the actions of morphine (10 mg/kg, IV) on ABG chemistry (pH, pCO2, pO2, sO2) and A -a gradient. L-serine ethylester (an oxygen atom replaces the sulfur; 500 mu mol/kg, IV), was ineffective in all studies. L-CYSee (500 mu mol/kg, IV) did not alter morphine (10 mg/kg, IV)induced sedation, but slightly reduced the overall duration of morphine (5 or 10 mg/kg, IV) -induced analgesia. In summary, L-CYSee rapidly overcame the effects of morphine on breathing and alveolar gas -exchange, while not affecting morphine sedation or early -stage analgesia. The mechanisms by which L-CYSee modulates morphine depression of breathing are unknown, but appear to require thiol-dependent processes.