The role of predrug signals in morphine analgesic tolerance: support for a Pavlovian conditioning model of tolerance.

According to a model of morphine tolerance, which emphasizes Pavlovian conditioning principles, tolerance results from an association between predrug environmental cues and the systemic effects of the drug. To assess this model, groups of rats were administered morphine on either three or nine occasions, with a complex environmental stimulus either paired or not paired with each injection. Control groups had equivalent experience with the environmental cue and injection procedure, but the injected substance was physiological saline. Subsequently, the analgesic effect of the opiate was tested in all subjects following administration of the drug in conjunction with the environmental cue. As expected on the basis of the conditioning model of tolerance, subjects with a pretest history of paired morphine administrations displayed analgesic tolerance, but subjects with a pretest history of unpaired administration displayed no evidence of such tolerance. The results suggest that prior demonstrations that the display of morphine tolerance is specific to the drug administration environment may be readily interpreted by a conditioning analysis of tolerance.