Reversal of morphine-induced respiratory depression with the μ1-opioid receptor antagonist naloxonazine engenders excitation and instability of breathing
Paediatrics
Reversal of morphine-induced respiratory depression with the μ1-opioid receptor antagonist naloxonazine engenders excitation and instability of breathing
Paediatrics

Reversal of morphine-induced respiratory depression with the μ1-opioid receptor antagonist naloxonazine engenders excitation and instability of breathing

Am J Physiol Lung Cell Mol Physiol. 2025 May 14. doi: 10.1152/ajplung.00045.2025. Online ahead of print.

ABSTRACT

The administration of opioid receptor antagonists is believed to overcome ventilatory depressant effects of opioids. Here we show that many ventilatory depressant effects of morphine are converted to excitatory responses after (mu1) μ1-opioid receptor blockade and that these responses are accompanied by ventilatory instability. We report in this study (1) the ventilatory responses elicited by morphine (10 mg/kg, IV) and (2) ventilatory responses elicited by a subsequent hypoxic-hypercapnic (H-H) challenge and return to room-air in male Sprague Dawley rats pre-treated with (i) vehicle, (ii) the centrally-acting selective μ1-opioid receptor antagonist, naloxonazine (1.5 mg/kg, IV), or (iii) the centrally-acting (delta1,2) δ1,2-opioid receptor antagonist, naltrindole (1.5 mg/kg, IV). The morphine-induced decreases in frequency of breathing, peak inspiratory flow, peak expiratory flow, EF50, inspiratory drive and expiratory drive, in vehicle-treated rats were converted to profound increases in naloxonazine pre-treated rats. The adverse effects of morphine on expiratory delay and apneic pause were augmented in naloxonazine-treated rats, and morphine increased ventilatory instability (i.e., non-eupneic breathing index) in naloxonazine-treated rats that was not due to increases in ventilatory drive. Subsequent exposure to a H-H challenge elicited qualitatively similar responses in both groups, whereas the responses upon return to room-air (e.g., frequency of breathing, inspiratory and expiratory times, end expiratory pause, relaxation time, expiratory delay, and non-eupneic breathing index) were substantially different in naloxonazine-treated versus vehicle-treated rats. The above effects of morphine were only marginally affected by naltrindole. These novel data highlight the complicated effects that μ1-opioid receptor antagonism exerts on the ventilatory effects of morphine.

PMID:40366705 | DOI:10.1152/ajplung.00045.2025