Associative morphine tolerance in the rat: examinations of compensatory responding and cross-tolerance with stress-induced analgesia.

The results of three experiments designed to examine the processes subserving associative tolerance to morphine's analgesic effects, as assessed by the tail-flick test, are reported. The experiments indicated that associative tolerance in male Holtzman rats was not subserved by conditioned compensatory responses but was cross-tolerant with an apparently nonopioid form of stress-induced analgesia (SIA). Experiment 1 showed that rats tested for morphine analgesia in a distinctive context that had been paired previously with morphine injections (5 mg/kg) were more tolerant than animals that had had this context explicitly unpaired with a series of morphine injections or animals that were drug-naive. There was no evidence of a conditioned compensatory response of hyperalgesia in animals given a saline injection in the presence of environmental stimuli that had been previously paired with morphine, even under test conditions designed to minimize the possibility of floor effects that might have obscured the detection of drug-compensatory hyperalgesia. Experiment 2 demonstrated that the footshock procedures used for stress induction produced an SIA that was not attenuated by naloxone (10 mg/kg). Experiment 3 replicated the associative tolerance phenomenon of Experiment 1 and again failed to find evidence of conditioned compensatory responses. It was found that animals exposed to footshock in the context that had been associated with morphine administration developed significantly less SIA than control animals. The relevance of these findings for associative models of drug tolerance is discussed.