Onset of tolerance to discriminative stimulus effects of morphine.

Experiments assessed the onset of tolerance to discriminative stimulus effects of morphine in rats treated repeatedly with twice daily doses of 10 mg/kg morphine. Saline and 3.2 mg/kg morphine were established as discriminative stimuli for food-reinforced fixed-ratio performances in several groups of rats, and initial ED50 values were determined for stimulus and rate-altering effects of morphine. To assess onset of tolerance, training was halted and 10 mg/kg doses of morphine were administered repeatedly at 12-h intervals. In separate experiments, ED50 values were redetermined after various treatment periods. One treatment with 10 mg/kg morphine did not alter the ED50 for stimulus effects of morphine, whereas treatment for one or three days increased the ED50 by approximately 2-fold. Comparisons with published data showed even greater tolerance when treatment lasted one or two weeks. Tolerance to stimulus effects of morphine generally was accompanied by tolerance to its rate-decreasing effects. Repeated treatment with morphine also produced cross-tolerance to morphine-like stimulus effects of methadone and buprenorphine. As with morphine itself, greater tolerance developed with longer treatment. These results suggest that tolerance to discriminative stimulus effects of morphine develops gradually, with magnitude of tolerance increasing as a function of treatment duration.