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 potential confound in the study of associative and nonassociative morphine tolerance development. Rats administered a series of morphine injections paired with a distinctive context environment can develop tolerance controlled associatively by the context. However, rats given morphine unpaired with the context may also develop some degree of tolerance. This study examined whether this tolerance represents an associative effect with animals using the injection ritual as a cue predictive of morphine delivery. Following 14 days of habituation to handling and injection stimuli, rats were given eight morphine injections (20 mg/kg, IP) explicitly paired or unpaired with a distinctive context. Animals were then tested for morphine analgesia in the context after either a 30-day rest condition or a 30-day period of daily saline injections. Analgesia was assessed by the tail-flick method, and tolerance was defined as the shift to the right of the dose-response curve of morphine-experienced relative to saline control animals. Paired animals across both retention conditions displayed tolerance, whereas tolerance retention in unpaired animals was observed only in those animals not given saline injections over the 30-day interval. Results support an associative interpretation of tolerance observed in unpaired conditions and suggest that the injection ritual may provide highly salient cues for the support of associative tolerance effects.