Alterations in the antagonism by naloxone of morphine-induced respiratory depression and analgesia after morphine pretreatment.

Mice were pretreated either acutely or chronically with morphine to test the effect of such pretreatments on the antagonism by naloxone of morphine-induced respiratory depression and analgesia and to compare the development of tolerance to the two effects. A s.c. injection of 20 mg/kg of morphine 6 hr before testing produced a shift of the apparent pA2 of morphine-naloxone for analgesia from 7.05 to 7.33, while the same pretreatment did not change the apparent pA2 for respiratory depression. However, s.c. implantation of a morphine pellet for 72 hr produced a shift in the apparent pA2 of morphine-naloxone for respiratory depression from 7.35 to 7.63, which represents less than a 2-fold increase in naloxone potency. The same pretreatment produced a further shift of the apparent pA2 for analgesia to 7.58, representing a greater than 3-fold increase in naloxone potency. After morphine pellet implantation mice showed a much greater degree of tolerance to morphine-induced analgesia than to respiratory depression. These results provide further evidence that narcotic-induced respiratory depression and analgesia are mediated by different receptor interactions.