Tolerance to morphine-like stimulus effects of mu opioid agonists

A. M. Young, G. Kapitsopoulos, M. M. Makhay

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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.

Original languageEnglish
Pages (from-to)795-805
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 1991


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