PT - JOURNAL ARTICLE AU - Young, A M AU - Kapitsopoulos, G AU - Makhay, M M TI - Tolerance to morphine-like stimulus effects of mu opioid agonists. DP - 1991 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 795--805 VI - 257 IP - 2 4099 - http://jpet.aspetjournals.org/content/257/2/795.short 4100 - http://jpet.aspetjournals.org/content/257/2/795.full SO - J Pharmacol Exp Ther1991 May 01; 257 AB - Experiments assessed the ability of repeated treatment with morphine to produce tolerance to morphine-like discriminative stimulus effects of buprenorphine, etorphine, methadone, morphine, and nalbuphine. Before treatment, each compound evoked full morphine-like stimulus effects in rats trained to discriminate saline and 3.2 mg/kg morphine. During treatment, training was halted and a dose of 10 mg/kg morphine administered every 12 h for 14-18 days. Repeated treatment with morphine increased the ED50 for stimulus control by etorphine, methadone or buprenorphine 2- to 4-fold and that for morphine 4.5-fold. Repeated treatment produced an insurmountable tolerance to the morphine-like stimulus effects of nalbuphine, so that a dose 150-fold higher than the initial ED50 evoked only 40% generalization. Treatment with a lower dose of morphine (10 mg/kg every 24 h) produced a short-lived surmountable tolerance to stimulus effects of nalbuphine. For etorphine, methadone and morphine, tolerance to morphine-like stimulus effects was accompanied by tolerance to rate suppressing effects. After treatment ended, the ED50 for stimulus control by etorphine, methadone or nalbuphine returned to initial values within 3 days; that for morphine, within 5 days; that for buprenorphine, within 10 days. These results demonstrate that repeated treatment with morphine produces cross-tolerance to compounds that exert morphine-like stimulus effects. Additionally, the results suggest that differences among these compounds in agonist efficacy may be revealed as differences in the degree of tolerance produced by morphine treatment.