ROLE OF DRUG-ADMINISTRATION CUES IN THE ASSOCIATIVE CONTROL OF MORPHINE-TOLERANCE IN THE RAT

This research investigated the role of injection procedures as a poten tial confound in the study of associative and nonassociative morphine tolerance development. Rats administered a series of morphine injectio ns paired with a distinctive context environment can develop tolerance controled associatively by the context. However, rats given morphine unpaired with the context may also develop some degree of tolerance. T his study examined whether this tolerance represents an associative ef fect with animals using the injection ritual as a cue predictive of mo rphine delivery. Following 14 days of habituation to handling and inje ction stimuli, rats were given eight morphine injections (20 mg/kg, IP ) explicitly paired or unpaired with a distinctive context. Animals we re then tested for morphine analgesia in the context after either a 30 -day rest condition or a 30-day period of daily saline injections. Ana lgesia was assessed by the tail-flick method, and tolerance was define d as the shift to the right of the dose-response curve of morphine-exp erienced relative to saline control animals. Paired animals across bot h retention conditions displayed tolerance, whereas tolerance retentio n in unpaired animals was observed only in those animals not given sal ine injections over the 30-day interval. Results support an associativ e interpretation of tolerance observed in unpaired conditions and sugg est that the injection ritual may provide highly salient cues for the support of associative tolerance effects.