Discriminative stimulus effects of reversible and irreversible opiate agonists: Morphine, oxymorphazone and buprenorphine

Pigeons were trained under a multiple-trial procedure to discriminate morphine (5.6 mg/kg) from saline. Morphine, oxymorphazone and buprenorphine each occasioned complete drug-appropriate responding in a dose-related manner and, at larger doses, suppressed responding completely. The order of potency as discriminative stimuli was buprenorphine > oxymorphazone > morphine; the potencies in suppressing responding were oxymorphazone > morphine > buprenorphine. Pretreatment with naltrexone (0.01-1.0 mg/kg) shifted the discrimination dose-effect curves to the right for all three compounds. When a discriminative effect was first established with morphine or oxymorphazone, the subsequent administration of naltrexone (0.01-0.32 mg/kg) completely and dose dependently antagonized the cue produced by each. Thus, oxymorphazone was not markedly different from morphine in its profile of action. Naltrexone up to 10.0 mg/kg failed to reverse completely the established discriminative effects of 0.32 mg/kg of buprenorphine, indicating that buprenorphine acts as an irreversible, morphine-like agonist in this behavioral situation. Buprenorphine had a much longer duration of action (3-4 days) than morphine (24 hr) or oxymorphazone (24-48 hr). Neither prolonged exposure to buprenorphine nor treatment with 100.0 mg/kg/day of morphine for 5 days produced tolerance to the discriminative or rate-suppressing effects of morphine. Buprenorphine also failed to antagonize either the discriminative or rate-suppressing effects of morphine. These data clearly demonstrate the irreversible morphine-like discriminative effects of buprenorphine and the reversible actions of morphine and oxymorphazone. These results also indicate that drug discrimination procedures may be valuable for the identification and characterization of irreversible agonists and antagonists.