Respiratory effects of opioid full and partial agonists in rhesus monkeys

Respiratory and behavioral effects of the mu selective opioids levorphanol (0.01-3.0 mg/kg), methadone (0.03-5.6 mg/kg) and codeine (0.3-30.0 mg/kg) and the mixed-action opioids buprenorphine (0.003-10.0 mg/kg), butorphanol (0.003-0.3 mg/kg) and nalbuphine (0.03-30.0 mg/kg) were studied in rhesus monkeys. In respiratory experiments, awake, seated monkeys wore plastic masks through which they breathed air or differing concentrations of CO2 mixed in air. Exposure to CO2 in air stimulated ventilation in a concentration-dependent manner. All opioids produced dose-dependent decreases in ventilation that were more pronounced as the concentration of CO2 increased. The highest doses of levorphanol, methadone, and butorphanol reduced the ventilatory stimulant effects of 5% CO2 in air by 85 to 90%, whereas the highest doses of nalbuphine, buprenorphine and codeine reduced the effects of 5% CO2 in air by only 50 to 75%. After presession butorphanol (0.01-0.1 mg/kg) or nalbuphine (1.0-3.0 mg/kg), levorphanol further reduced the ventilatory stimulant effects of 5% CO2 mixed in air, with some evidence of dose-effect flattening. However, pretreatment with buprenorphine (1.0-10.0 mg/kg) and the highest dose of nalbuphine (10.0 mg/kg) attenuated the effects of 10.0 mg/kg levorphanol, indicative of antagonism. In behavioral experiments, all drugs produced dose-related decreases in responding under a 30-response fixed-ratio schedule. The highest doses of levorphanol, methadone, codeine, and butorphanol nearly abolished responding in all subjects, whereas buprenorphine and nalbuphine most often reduced response rates by no more than 50%. Except for codeine, rank orders of potency were the same in behavioral and respiratory experiments. The lesser effects of nalbuphine and buprenorphine on venlilation, in conjunction with their levorphanol-anlagonist effects, suggest their limited mu agonist efficacy at sites mediating the respiratory-depressant effects of opioids.