L-Cysteine Ethyl Ester May Overcome Morphine-Induced Respiratory Depression by Activating Muscarinic Receptors

Background/Objectives: Opioids inhibit breathing that can lead to fatal overdose, highlighting the need for testing effective countermeasure agents and potential mechanisms of action. Here we examined the role muscarinic cholinergic receptors play in the ability of L-cysteine ethyl ester (L-CYSee) to overcome the deleterious effects of morphine on ventilatory parameters in male Sprague Dawley rats and the ventilatory responses during a subsequent hypoxic-hypercapnic (HH) challenge. Methods: Ventilatory parameters were measured by whole body plethysmography. Results: The injection of the muscarinic receptor antagonist, atropine (1.0 mg/kg, IV), elicited an array of ventilatory responses (e.g., an increase in frequency of breathing coupled with a fall in tidal volume). Injection of morphine (10 mg/kg, IV) to vehicle-treated rats elicited a depression of breathing, including sustained decreases in tidal volume, minute ventilation, peak inspiratory flow, and peak inspiratory and expiratory drives, which were associated with marked increases in end inspiratory pause (EIP) and end expiratory pause (EEP), expiratory flow at 50% expired tidal volume (EF₅₀), and rate of achieving peak expiratory flow (Rpef). Most effects of morphine (10 mg/kg, IV) were not altered in atropine-treated rats, except that increases in EIP, EEP and Rpef were reduced. Subsequent injections of L-CYSee (2 × 500 μmol/kg, IV given 15 min apart) overcame the adverse actions of morphine on ventilatory parameters in vehicle-treated rats. The effects of L-CYSee, such as reversal of the effects of morphine on frequency of breathing, tidal volume and minute ventilation, were markedly reduced in atropine-treated rats. The ability of L-CYSee to reverse the adverse effects of morphine to a HH gas challenge was markedly diminished in atropine-treated rats. Conclusions: These findings demonstrate that muscarinic receptors play a vital role in the ability of L-CYSee to overcome the deleterious effects of morphine.