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°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, ethyl-ketazocine, 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, ethyl-ketazocine, 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.