Nitrosyl factors play a vital role in the ventilatory depressant effects of fentanyl in freely moving guinea pigs

Abstract

An understanding of intracellular mechanisms by which fentanyl and other synthetic opioids exert adverse effects on breathing is needed. Using freely moving adult male guinea pigs, we administered the nitric oxide synthase (NOS) inhibitor, L-NAME (N^G-nitro-L-arginine methyl ester), to determine whether nitrosyl factors, such as nitric oxide and S-nitrosothiols, play a role in fentanyl-induced respiratory depression. Ventilatory parameters were recorded by whole body plethysmography to determine the effects of fentanyl (75 μg/kg, IV) in guinea pigs that had received a prior injection of vehicle (saline), L-NAME or the inactive D-isomer, D-NAME (both at 50 μmol/kg, IV), 15 min beforehand. L- and D-NAME elicited minor effects on most parameters, including frequency of breathing, tidal volume and minute ventilation, although L-NAME did decrease end expiratory pause and non-eupneic breathing index (NEBI). Subsequent injection of fentanyl in guinea pigs pre-treated with vehicle produced profound and sustained reductions in frequency, tidal volume, minute ventilation, peak inspiratory flow, and inspiratory and expiratory drives, while increasing inspiratory time, expiratory time, end inspiratory pause, and NEBI. These ventilatory depressant effects of fentanyl seen in guinea pigs pre-treated with vehicle were markedly diminished in guinea pigs pre-treated with L-NAME. Moreover, the adverse effects of fentanyl on many recorded breathing parameters were converted to stimulatory effects. In contrast, D-NAME did not alter any of the effects of fentanyl on breathing. This study is the first to characterize the role nitrosyl factors play in the intracellular mechanisms involved in fentanyl-induced respiratory depression in guinea pigs.