The opioid receptor antagonist naloxonazine uncovers the pronounced ventilatory stimulant effects of fentanyl in freely-moving rats

We previously reported that administration of an opioid receptor antagonist elicits pronounced increases in minute ventilation in rats where the respiratory effects of formerly administered fentanyl had resolved. Thus, fentanyl induces the activation of an opioid receptor-dependent inhibitory system and a non-opioid receptor-dependent excitatory system - two systems with on-going counter-balancing effects on breathing. The objective of the present study was to determine whether administration of the potent, centrally-acting opioid receptor antagonist, naloxonazine (NLZ), during fentanyl-induced suppression of respiration, elicits an overshoot of breathing - above baseline values - suggesting the presence of an on-going excitatory ventilatory control system. The intravenous administration of 25, 50 or 75 μg/kg doses of fentanyl to separate groups of male Sprague Dawley rats elicited pronounced dose-dependent reductions in frequency of breathing, tidal volume, and minute ventilation. NLZ (1.5 mg/kg, IV) given 5 min after the injection of 25, 50 or 75 μg/kg doses of fentanyl - the timepoint in which the ventilatory depressant effects of fentanyl were most pronounced - elicited overshoots in frequency of breathing, tidal volume, and minute ventilation, as well as many other parameters, including, peak inspiratory and expiratory flows and inspiratory and expiratory drives. This overshoot in breathing, which lasted for 20-30 min, was associated with minor increases in the non-eupneic breathing index (NEBI), suggesting that the responses were not accompanied by unwanted effects on respiratory timing and mechanics. Understanding the mechanism(s) by which this non-opioid receptor-dependent excitatory ventilatory system acts may lead to the development of novel ventilatory stimulants.