Effect of Interdose Interval on the Development of Associative Tolerance to Morphine in the Rat: A Dose-Response Analysis

Three experiments examined the effect of interdose interval (IDI) on the development and retention of associative tolerance to the analgesic effects of morphine. Tolerance was indexed as the magnitude of the shift to the right of the dose-response curve (DRC). Experiment 1 showed that associative tolerance was characterized by a parallel shift in the DRC to the right in rats that had received morphine explicitly paired with the distinctive test context at 12-, 24-, and 96-hr IDIs. Associative tolerance was attenuated at the shortest IDI. Experiment 2 revealed that associative tolerance that developed in the 12- and 96-hr IDI conditions showed comparable levels of retention at 30 days. Experiment 3 showed that associative tolerance was not disrupted by the administration of unsignaled doses of morphine 12 hr before each drug-context pairing. Theoretical and methodological implications of the data are discussed.