Discriminative stimulus effects of naltrexone in narcotic-naive and morphine-treated pigeons

Narcotic-naive pigeons were trained to discriminate naltrexone (32 mg/kg) from saline by reinforcing responses on one of two response keys. All of the pigeons responded reliably on the naltrexone- or saline-appropriate key after an average of 73 training sessions. The administration of naltrexone (3.2-56.0 mg/kg) or naloxone (10.0-56.0 mg/kg) resulted in dose-related responding on the naltrexone-appropriate key such that 90% or more of the total responses in session were made on the naltrexone-appropriate key after administration of the highest doses (≥32 mg/kg). In contrast, the administration of certain other narcotic antagonists including cyclazocine, diprenorphine, nalorphine and the benzomorphan narcotic antagonists, MR 2266, MR 2267, MR 1453, MR 1452 and WIN 44,441, did not produce comparable amounts of naltrexone-appropriate responding. Thus, the discriminative stimulus effects of naltrexone in narcotic-naive animals appeared to be unrelated to its ability to antagonize opiates. The pigeons were then administered morphine (100 mg/kg/day) and trained to discriminate between either 0.1 or 0.3 mg/kg of naltrexone and saline. Naltrexone and naloxone were 320 and 100 times more potent, respectively, in producing naltrexone-appropriate responding and response-rate suppression in morphine-treated than in normal pigeons. In contrast to the results obtained in narcotic-naive pigeons, cyclazocine, nalorphine, diprenorphine, MR 2266, MR 1452 and WIN 44,441 produced dose-related naltrexone-appropriate responding in morphine-treated pigeons. Non-narcotic compounds and dextroisomers of narcotic antagonists (MR 2267 and MR 1453) produced predominantly saline-appropriate responding or intermediate levels of naltrexone-appropriate responding in both narcotic-naive and morphine-treated pigeons. The observation that narcotic antagonists share discriminative stimulus effects in morphine-treated, but not in naive pigeons, suggests that the chronic administration of morphine alters, qualitatively, the stimulus effects of narcotic antagonists.