AGONIST AND ANTAGONIST EFFECTS OF MIXED ACTION OPIOIDS IN THE PIGEON DRUG DISCRIMINATION PROCEDURE - INFLUENCE OF TRAINING DOSE, INTRINSIC EFFICACY AND INTERANIMAL DIFFERENCES

The stimulus effects of selective, high efficacy mu opioids and mixed action opioids with varying degrees of intrinsic efficacy at the mu re ceptor were examined in pigeons trained to discriminate between saline and either 0.056 (low) or 0.18 (high) mg/kg of fentanyl. The stimulus profiles produced by the various opioids could be separated into thre e groups: 1) opioids that substituted completely for both training dos es of fentanyl, with steep slopes and little interanimal differences i n the lowest dose (lowest discriminable dose) that produced complete s ubstitution (fentanyl, morphine and /-alpha-acetylmethadol); 2) opioid s that substituted completely for the low training dose and produced h igh levels of substitution for the high training dose, with relatively shallow slopes and interanimal differences in the lowest discriminabl e dose (butorphanol, buprenorphine, ethylketocyclazocine, ketocyclazoc ine, proxorphan, (-)-pentazocine and (-)-metazocine); and 3) opioids t hat substituted completely for the low training dose, with relatively shallow slopes and large interanimal differences in the lowest discrim inable dose. Each of these opioids also antagonized the high-dose fent anyl stimulus with large interanimal differences in the lowest antagon ist dose (nalbuphine, nalorphine, (-)-cyclorphan, (-)-cyclazocine, (-) -n-ally-normetazocine and levallorphan). These patterns of substitutio n and antagonism most likely reflect differences in the intrinsic effi cacy of these drugs at the mu receptor, with low intrinsic efficacy as sociated with shallow dose-effect functions, large interanimal differe nces in the drug's lowest discriminable dose and low levels of substit ution for the high-dose fentanyl stimulus. During antagonism tests wit h naloxone, two patterns were observed: 1) opioids against which nalox one had apparent pA2 values of approximately 7.0, with little interani mal differences and with the slopes of the Schild plots approximating -1.0 (fentanyl and morphine) and 2) opioids against which naloxone had apparent pA2 values an order of magnitude higher, with large interani mal differences and with the slopes of Schild plots being relatively s hallow (butorphanol, nalbuphine, nalorphine and levallorphan). The pre sent findings emphasize the importance of training dose, intrinsic eff icacy and interanimal differences when analyzing drug discrimination d ata.