Opiate agonist-antagonist interactions: Application of a three-key drug discrimination procedure

Pigeons were trained to discriminate among i.m. injections of morphine (5.6 mg/kg), saline and naltrexone (10.0 mg/kg) in a three-key operant procedure with food reinforcement. Animals acquired the discrimination; each training condition occasioned responding on the injection-appropriate key, and the effects of morphine and naltrexone were dose-dependent. The opiate agonists ethylketazocine, buprenorphine and pentazocine substituted completely for morphine, and the opiate antagonist naloxone substituted completely for naltrexone. Meperidine, dextrorphan, β-funaltrexamine, diprenorphine and nalorphine produced responding predominantly on the saline key, indicating that these compounds do not share completely discriminative properties with naltrexone or morphine in the pigeon. Small doses of naltrexone (0.01 and 0.1 mg/kg) shifted the morphine discrimination dose-effect curve in parallel to the right, without producing naltrexone-appropriate responding. Larger doses of naltrexone (1.0-10.0 mg/kg) prevented the discriminative effect of morphine and generated dose-dependent naltrexone-appropriate responding. The prior administration of small doses of morphine (0.1 and 1.0 mg/kg) enhanced the discriminative effects of naltrexone. Some dose combinations of naltrexone and morphine produced responding on all three keys, up to doses that suppressed behavior. The study of agonist-antagonist interactions may be aided by the use of these procedures, as descriptions of insurmountable antagonism may be complemented by the identification of stimulus conditions associated with the antagonist, as well as those conditions that represent novel stimulus states.