Modulation of the discriminative stimulus effects of cocaine by the μ agonist morphine, the K agonist U 50,488, and the δ agonist BW 373U86 was investigated in squirrel monkeys using a two-lever drug discrimination procedure. Monkeys initially were trained to discriminate intramuscular injections of 0.3 or 0.56 mg/kg cocaine from vehicle and subsequently retrained to discriminate a 3− to 5.6-fold lower dose of cocaine (0.1 or 0.18 mg/kg). After retraining, dose-response functions for the discriminative stimulus effects of cocaine were shifted to the left and ED50values were reduced 2− to 6-fold compared to values obtained with the higher training doses. In drug substitution experiments, morphine (0.03–1.0 mg/kg), U 50,488 (0.1–3.0 mg/kg) and BW 373U86 (0.001–0.1 mg/kg) did not reproduce the discriminative stimulus effects of the low training doses of cocaine, although U 50,488 engendered a majority of responses on the cocaine-associated lever in two of three monkeys. In drug interaction experiments, pretreatment with morphine (0.3 mg/kg) potentiated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the left and ED50values were reduced 3− to 7-fold. Pretreatment with U 50,488 (0.3 mg/kg), on the other hand, attenuated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the right and ED50values were increased approximately 4-fold. The cocaine-modulating effects of morphine and U 50,488 in these experiments were qualitatively similar to those observed previously when the monkeys were trained to discriminate higher doses of cocaine. In contrast to the effects of the μ and K agonists, pretreatment with BW 373U86 (0.01 or 0.03 mg/kg) did not systematically alter the discriminative stimulus effects of cocaine regardless of training dose.