Dose-response analyses of associative tolerance to nicotine analgesia in the rat: tail-flick and hot-plate tests.

This study is the first to demonstrate associative tolerance to nicotine's analgesic effects as a shift in the dose-response curve (DRC) to the right. The subjects were 43 experimentally naive, male Sprague Dawley rats (Rattus norvegicus) randomly assigned to 2 groups. Home cage rats (HC; n = 21) received a series of 1 mg/kg nicotine doses explicitly unpaired with the distinctive context, whereas distinctive context rats (DC; n = 22) were injected with nicotine explicitly paired with the distinctive context. Rats in each of the 2 groups were randomly assigned to 1 of 3 nicotine testing doses to construct DRCs. The DRC of the rats that received nicotine in the distinctive context was shifted to the right of the DRC of rats that had had as much exposure to nicotine but had never experienced nicotine in the distinctive context. DC rats required nearly twice as much nicotine as HC rats to produce the same DRC. The discussion describes the implications of the results for theories of drug tolerance and nicotine addiction.