Characterization of the acute tolerance and dependence to morphine-induced respiratory depression in decerebrate cats

Abstract

Acute tolerance to the respiratory depression was produced in decerebrate cats by injecting six consecutive doses of morphine, 2 mg/kg each, at one hour interval. The course of tolerance was examined independently for frequency and tidal volume, in resting as well as in CO2-stimulated breathing.

Regarding respiratory frequency, maximal depression was induced by the first dose of morphine; subsequent doses did not depress frequency any further. Recovery toward control level was initiated after the second dose. Maximal tidal volume depression was observed after two or three doses of morphine; the values remained at the lowest level for the rest of the experiment. Cross-tolerance between morphine and fentanyl was readily obtained, for frequency as well as for tidal volume. Pentobarbital did not show cross-tolerance with the analgetics.

Acute dependence was unmasked by naloxone, 1 mg/kg. Reversion of the depression and overshoot were observed, especially on the part of respiratory frequency. Naloxone shifted to the left of the control curve and increased the slope of the CO2-ventilation relationship. This effect demonstrates the hyper-excitability created on the respiratory center during the development of dependence.