The cystathionine-γ-lyase inhibitor <scp>DL</scp>-propargylglycine augments the ability of <scp>L</scp>-cysteine ethyl ester to overcome the adverse effects of morphine on breathing

l-cysteine ethyl ester (l-CYSee) overcomes adverse effects elicited by systemic injection of morphine on ventilatory parameters and arterial blood-gas chemistry in rats. l-CYSee or l-cysteine, resulting from the deesterification of l-CYSee, may enter enzymatic cascades that produce the ventilatory stimulant molecule, hydrogen sulfide (H₂S). dl-propargylglycine (dl-PROP) is an inhibitor of cystathionine-γ-lyase (CSE)-mediated conversion of l-cysteine to H₂S and has been widely used <i>in vivo</i>. We examined whether l-CYSee (2 injections × 500 µmol/kg, IV)-induced reversal of the changes in ventilation elicited by morphine (10 mg/kg, IV) in freely moving male Sprague Dawley rats was altered by prior administration of dl-PROP (25 mg/kg, IV). The major findings were <i>1</i>) the effects of morphine on ventilatory parameters were not affected by subsequent injection of dl-PROP; <i>2</i>) first injection of l-CYSee elicited a prompt reversal of the adverse effects of morphine that was more pronounced in dl-PROP-treated than vehicle-treated rats; and <i>3</i>) the actions of the second injection of l-CYSee were dramatically augmented in dl-PROP-treated rats. In addition, the changes in many of the ventilatory parameters during a subsequent hypoxic-hypercapnic (HH) gas challenge were augmented substantially by dl-PROP. This study demonstrates that <i>1</i>) inhibition of CSE with dl-PROP does not affect the ventilatory actions of morphine, <i>2</i>) reversal effects of l-CYSee were augmented by blockade of CSE, and <i>3</i>) blockade of CSE augments the ventilatory responses to HH gas challenge in morphine-treated rats. These unexpected findings suggest that the CSE-dependent production of H₂S from l-CYSee countermands l-CYSee reversal of morphine-induced respiratory depression in rats.<b>NEW & NOTEWORTHY</b> The ability of l-cysteine ethyl ester (l-CYSee) to overcome the adverse effects of morphine on breathing is exaggerated by inhibition of cystathionine-γ-lyase (CSE), suggesting that conversion of l-CYSee or l-cysteine to H₂S countermands the effects of l-CYSee against morphine.