Effects of morphine, naloxone, buprenorphine, butorphanol, haloperidol and imipramine on morphine withdrawal signs in cynomolgus monkeys

Abstract

This study was conducted to characterize the opiate dependence potential 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 directly compared. Six male cynomolgus monkeys were maintained on morphine (3.0 mg/kg, q.i.d.) for 6 months. On evaluation days, monkeys were scored 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 micrograms/kg), butorphanol (0.01, 0.1, 1.0 or 3.2 mg/kg), haloperidol (0.01, 0.05 or 0.1 mg/kg), imipramine (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 precipitation experiment either saline or 0.01 or 0.1 mg/kg butorphanol was administered 2 h after the last maintenance dose of morphine. In the single dose suppression test, morphine completely suppressed most withdrawal signs while naloxone increased the severity of withdrawal. All doses of buprenorphine increased many withdrawal signs such as backward gait, rearing, chafing face, chain biting, vomiting, masturbation, and vocalizations after intimidation. Only a few signs were reduced, but the overall withdrawal scores were not significantly increased. Low doses of butorphanol suppressed some signs while the highest dose almost completely eliminated all withdrawal signs. Butorphanol also failed to precipitate opiate withdrawal, and actually reversed the signs present in the saline-treated monkeys. Imipramine and haloperidol had little effect on the morphine withdrawal syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)