Ventilation in morphine-maintained rhesus monkeys. II: Tolerance to the antinociceptive but not the ventilatory effects of morphine.

The antinociceptive and ventilatory effects of morphine and other opioid agonists were determined in three rhesus monkeys during a period of morphine maintenance, as well as before and after the chronic exposure to morphine. Before the onset of the daily dosing regimen, morphine increased tail-withdrawal latencies from 50 degrees C water, with an ED50 of 6.4 +/- 2.1 mg/kg. Daily injection of 3.2 mg/kg morphine produced a rightward displacement of the morphine dose-response curve, increasing the ED50 of morphine to 28.4 +/- 12.3 mg/kg. Doubling the daily morphine dose to 6.4 mg/kg resulted in a further shift to the right of the dose-response curve of morphine. After cessation of the daily dosing regimen, the morphine dose-response curve for producing antinociceptive effects returned toward baseline. The antinociceptive effects of the kappa opioid agonist, ethylketazocine, were similar during the period of daily exposure to morphine, and after cessation of the daily dosing regimen. Before the onset of the daily dosing regimen, morphine, ethylketazocine, fentanyl, butorphanol and nalbuphine decreased ventilation in the presence of air or air mixed with CO2. The baseline ED50 value of morphine for decreasing minute volume in the presence of 5% CO2 was 2.9 +/- 0.8 mg/kg. The ventilatory effects of morphine and other mu opioid agonists tested were not attenuated during the daily morphine-dosing regimen. After 40 weeks of daily injections of 3.2 mg/kg morphine, the ED50 of morphine for decreasing minute volume in 5% CO2 was 2.3 +/- 1.0 mg/kg, and when the daily dose was doubled to 6.4 mg/kg morphine, the ED50 of morphine was 1.5 +/- 0.5 mg/kg. The ventilatory depressant effects of the daily injection 3.2 mg/kg morphine were also unchanged during morphine maintenance. The differential development of tolerance to the antinociceptive and ventilatory effects of morphine demonstrates a separation of these two mu opioid agonist effects in rhesus monkeys.