EFFECTS OF MORPHINE, NALOXONE, BUPRENORPHINE, BUTORPHANOL, HALOPERIDOL AND IMIPRAMINE ON MORPHINE-WITHDRAWAL SIGNS IN CYNOMOLGUS MONKEYS

This study was conducted to characterize the opiate dependence potenti al of a number of opiate and non-opiate psychoactive drugs in morphine -dependent cynomolgus monkeys (Macaca fascicularis). In addition, the agonist/antagonist profiles of buprenorphine and butorphanol were dire ctly compared. Six male cynomolgus monkeys were maintained on morphine (3.0 mg/kg, q.i.d.) for 6 months. On evaluation days, monkeys were sc ored for opiate withdrawal signs 18 h after the last dose of morphine. Single dose suppression studies were conducted by giving subcutaneous injections of morphine (3 or 6 mg/kg), naloxone (0.01, 0.05 or 0.1 mg /kg), buprenorphine (1, 3, 10, 30 or 100 mu g/kg), butorphanol(0.01, 0 .1, 1.0 or 3.2 mg/kg), haloperidol (0.01, 0.05 or 0.1 mg/kg), imiprami ne (2, 5 or 10 mg/kg) or saline and measuring the number and frequency of withdrawal signs that appeared over a 2-h period. In a separate pr ecipitation experiment either saline or 0.01 or 0.1 mg/kg butorphanol was administered 2h after the last maintenance dose of morphine. In th e single dose suppression test, morphine completely suppressed most wi thdrawal signs while naloxone increased the severity of withdrawal. Al l doses of buprenorphine increased many withdrawal signs such as backw ard gait, rearing chafing face, chain biting, vomiting, masturbation, and vocalizations after intimidation. Only a few signs were reduced, b ut the overall withdrawal scores were not significantly increased. Low doses of butorphanol suppressed some signs while the highest dose alm ost completely eliminated all withdrawal signs. Butorphanol also faile d to precipitate opiate withdrawal, and actually reversed the signs pr esent in the saline-treated monkeys. Imipramine and haloperidol had li ttle effect on the morphine withdrawal syndrome. These data suggest bu prenorphine exerts only opioid antagonistic activity and butorphanol e xerts only opioid a,antagonistic activity over a wide range of doses s tudied in morphine-dependent cynomolgus monkeys.