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An analysis of the effects of contextual cues on the development of morphine tolerance in rats.

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Department of Psychology, Kwansei Gakuin University, Nishinomiya, 662-8501 Japan.


Tolerance to morphine analgesia was determined daily by exposing rats either to the same box or to different boxes by a repeated administration of morphine (5 mg/kg). In the Acquisition Phase, the rats received either morphine or saline in the same or different boxes for four consecutive days, and the process of tolerance development was assessed by a hot-plate test. Marked tolerance developed in the group exposed to the same contextual cue, whereas tolerance was attenuated in the group exposed to different cues. In the Extinction Phase, all rats received saline injections in the box exposed on Day 1 for four days. On the first day, hyperalgesia was observed only in the rats injected with morphine in the same contextual cue. In the Retest Phase, the rats underwent a second morphine injection and to some extent showed recovery from tolerance. In the Acquisition Phase, the number of animals showing abnormal activity with morphine injection increased monotonically in the group that was administered morphine in the same box (Group M-S) before injection, but in the group administered the drug in different boxes (Group M-D), no systematic development of the activity occurred. These results indicate that the hindering of a rat's ability to associate with environmental cues under the effect of morphine slows the development of tolerance, and the withdrawal and anticipatory symptoms, and the tolerance of morphine involves psychological and pharmacological factors.

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