Effect of number of conditioning trials on the development of associative tolerance to morphine.

The acquisition of associative tolerance to the analgesic effects of morphine was investigated by giving independent groups of rats 1, 3, 5, 8, 14, 20, or 30 administrations of drug either explicitly paired or unpaired with a distinctive context. Tolerance, assessed on a tail-flick device using dose-response curve (DRC) methodology, developed more rapidly and reached greater magnitude when morphine and the distinctive context were explicitly paired rather than explicitly unpaired. Tolerance magnitude in both conditions reached a maximum at eight conditioning sessions. It is argued that the tolerance found in both treatment groups was associatively controlled. The function of handling and injection cues as conditioned stimuli, and the deleterious effects of latent inhibition and partial reinforcement on conditioned excitation and conditioned inhibition are discussed.