Associative tolerance to nicotine analgesia in the rat: tail-flick and hot-plate assays

Abstract

Previous demonstrations of associative tolerance to the analgesic effects of nicotine have been confounded by either (1) novelty-induced stress in the tolerance test-session, or (2) instrumental learning of the test response throughout the tolerance development phase, or both. In Experiment 1, Sprague-Dawley male rats (N = 32) were habituated to mock tests and then injected with various nicotine doses and tested for nociception. It was found that nicotine produced analgesia in a dose dependent manner. In Experiment 2, rats (N = 35) received a series of nicotine injections either explicitly paired or explicitly unpaired with a distinctive test-context. Rats that received nicotine explicitly paired with a distinctive context (DC) exhibited shorter response latencies to noxious stimuli (i.e., tail-flick and hot-plate test) than animals receiving an identical number of nicotine injections explicitly unpaired (HC) with the distinctive context and than saline control animals. This context effect can be interpreted as being caused by associative learning. In Experiment 3 (N = 43), the context effect found in Experiment 2 was replicated by testing independent groups of rats with different nicotine doses. That is, the context effect was demonstrated in a dose dependent manner, as evidenced by a shift to the right of the dose-response curve of DC animals with respect to HC animals.