Discriminative stimulus effects of naltrexone in morphine-treated rhesus monkeys

Three adult, female rhesus monkeys responded under a fixed-ratio 5 schedule of stimulus-shock termination while discriminating between s.c. injections of saline and naltrexone (0.01 mg/kg). In addition, monkeys received daily injections of morphine (1.78 or 3.2 mg/kg) 3 hr before experimental sessions. With increasing doses of naltrexone monkeys switched in a dose-related manner from the saline to the naltrexone lever; complete generalization (greater than 80% responding on the naltrexone lever) occurred in all monkeys at doses of naltrexone larger than 0.0032 mg/kg. Doses of naltrexone that produced responding on the drug lever also produced effects typically observed during opioid withdrawal (e.g., miosis and salivation). Compounds with opioid mu antagonist effects under other conditions (e.g., nalorphine) substituted for naltrexone whereas a wide variety of opioid agonists (e.g., morphine, U-50,488 and butorphanol) as well as nonopioids (e.g., pentobarbital and ketamine) produced responding predominantly on the saline lever. Monkeys also switched to the naltrexone lever in a time-related manner after the daily injection of morphine with complete generalization occurring between 8 and 27 hr after morphine. Among a variety of opioid and nonopioid compounds, including drugs used in the treatment of opioid abuse (e.g., clonidine), only compounds with mu agonist actions under other conditions produced a switch in responding from the naltrexone to the saline lever in 27-hr morphine-abstinent monkeys. These results suggest single, daily injections of morphine are sufficient to produce dependence in rhesus monkeys and indicate further drug discrimination studies in morphine-treated rhesus monkeys might be pharmacologically more specific than observational procedures.