Tolerance and cross-tolerance to the discriminative stimulus properties of fentanyl and morphine

M. W. Emmett-Oglesby, T. S. Shippenberg, A. Herz

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The investigation tested the hypothesis that tolerance would develop to the discriminative stimulus properties of fentanyl upon discontinuation of discrimination training and injection of fentanyl in doses larger than the training dose. Rats were trained to discriminate an injection of fentanyl, 0.04 mg/kg, from saline using a two-lever choice procedure with food as a reinforcer. Given acutely, morphine substituted for fentanyl and was 100-times less potent. Subsequently, training was stopped, and fentanyl, 0.08 mg/kg, was injected every 12 hr for 1 week. This procedure did not produce tolerance nor did tolerance occur when fentanyl, 0.16 mg/kg every 24 hr, was continued for an additional week. In contrast, a dose of morphine (8.0 mg/kg) that was equated for efficacy to the 0.08-mg/kg dose of fentanyl produced both tolerance to the morphine stimulus and cross-tolerance to the fentanyl stimulus after 3 to 4 days of administration. In an additional experiment, the time course for detection of fentanyl was found to be significantly shorter than the time course for the detection of morphine. These results suggest that the present, as well as a previous, report of failure to find tolerance to the stimulus properties of fentanyl is perhaps attributable to fentanyl's brief duration of action. To test this hypothesis, 16 rats were trained to discriminate fentanyl, 0.04 mg/kg, and dose-effect data were obtained for the generalization of fentanyl and the substitution of morphine for this discriminative stimulus. Subsequently, training was stopped and fentanyl was injected for 4 days in a design that called for injection of 0.12 mg/kg every 6 hr. This dosing regimen produced tolerance to the fentanyl stimulus and cross-tolerance to the morphine stimulus. Thus, tolerance can be obtained to the discriminative stimulus properties of fentanyl if dosing intervals are sufficiently brief.

Original languageEnglish
Pages (from-to)17-23
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 1988


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