[The effects of flumazenil or bicuculline on the respiratory depression by morphine]

The effects of intravenous administration of flumazenil (n = 6) or bicuculline (n = 6) on the discharge of the phrenic nerve were studied following vagotomy in pentobarbital anesthetized mechanically ventilated rats. Morphine (0.4 mg.kg-1.min-1) was administrated until the respiratory rate decreased to about a half of the baseline respiratory rate. In this state, we first administered flumazenil (0.25 mg.kg-1) or bicuculline (0.4 mg.kg-1), intravenously and then administered naloxone (0.02 mg) intravenously in the two groups. The increase of inspiratory time from 0.7 +/- 0.1 to 2.0 +/- 0.5 s by morphine recovered to 0.8 +/- 0.2 s by bicuculline and to 0.6 +/- 0.1 s by naloxone. The increase of inspiratory time from 0.7 +/- 0.1 to 1.7 +/- 0.3 s by morphine, and to 2.1 +/- 0.5 s by flumazenil recovered to 0.6 +/- 0.1 s by naloxone. Expiratory time did not change during each drug administration in the two groups. The decrease of respiratory rate from 44 to 23 +/- 4 breaths.min-1 by morphine recovered to 37 +/- 5 breaths.min-1 by bicuculline and to 42 +/- 2 breaths.min-1 by naloxone. The decrease of respiratory rate from 45 +/- 3 to 22 +/- 6 breaths.min-1 by morphine, and to 18 +/- 4 breaths.min-1 by flumazenil recovered to 46 +/- 3 breaths.min-1 by naloxone. Amplitude of integrated phrenic nerve discharge increased to 125 +/- 42% by bicuculline and to 175 +/- 93% by naloxone compared to the baseline values. The decrease of amplitude to 54 +/- 18% by flumazenil recovered to 125 +/- 42% by naloxone. These results suggest that bicuculline not flumazenil antagonizes the respiratory depression of morphine by increasing the respiratory rate and respiratory movement.