Ventilatory depression in naive and tolerant rats in relation to plasma morphine concentration

1 The disappearance of morphine from specially formulated pellets containing 75 mg morphine base was measured for 10 days after they were implanted into adult rats; the morphine content decreased at a rate of 5 mg pellet daily.2 From the 2nd to the 6th day of implantation the plasma morphine concentration increased but by the 10th day had declined to only one half the concentration found on day 6.3 Six and 24 h after the pellets were removed from 6 day implanted animals the plasma concentration of morphine amounted to only one quarter to one sixth of the amount in the plasma, respectively, of animals with pellets intact.4 The pulmonary minute volume of naive and implanted rats was depressed by morphine in proportion to the plasma morphine concentration. Less depression was produced by intravenous morphine in the implanted rats than in the naive animals; the greater morphine tolerance displayed by the implanted animals could be shown by the third day of implantation and appeared to be maintained to the 10th day.5 The pulmonary minute volume of implanted rats on the 6th day was much less than the pulmonary minute volume of naive rats. Six and 24 h after the pellets were removed the pulmonary minute volume increased as the plasma morphine concentration decreased.6 The effects on the pulmonary minute volume produced by the slow release of morphine from the implanted pellets was not changed by the development of tolerance while the effects of morphine produced by rapid injection were diminished by the development of tolerance; the different effects of morphine are accordingly linked to the mode of administration.7 We conclude that the action of morphine on the pulmonary minute volume in tolerant rats following rapid injection is fundamentally different from its action following its slow release from implanted pellets, possibly due to differences in access to an undefined neuronal site.