Associative and nonassociative tolerance: the effects of dose and interdose interval

Two experiments examined the effects of dose and interdose interval (IDI) on associative and nonassociative tolerance to morphine analgesia in rats. Associative contingencies were manipulated by administering low (5 mg/kg) or high (20 mg/kg) doses of morphine explicitly paired or unpaired with a distinctive context. Nonassociative processes were manipulated by administering morphine at a short (6-h) or long (96-h) IDI. Tolerance was assessed as shifts in morphine dose-response curves on the tail-flick test. Animals in the long IDI conditions showed considerable context-specific tolerance. Tolerance in the short IDI conditions was not influenced by contextual contingencies at the immediate test (Experiment 1) and showed no retention over a 30-day interval (Experiment 2), suggesting this tolerance was nonassociative. The impact of massed exposure to morphine and context on the disruption of learning at the short IDI is discussed.