State Dependent Learning and Morphine Tolerance

On the basis of a Pavlovian conditioning analysis of morphine tolerance, cues signaling the systemic effects of morphine come to elicit conditional pharmacological responses that attenuate the effect of the drug. Experiments were conducted to evaluate the relevance of this analysis to recent reports that morphine-experienced rats, anesthetized with pentobarbital prior to a final test injection of morphine, do not display the analgesic tolerance seen in nonanesthetized rats. It was hypothesized that such pentobarbital blockage of morphine tolerance represents an instance of state-dependent learning: the barbiturate alters predrug cues so that the final, barbiturate-signaled morphine administration is presented in the context of different signals than those accompanying pretest administrations of the opiate. Results of the present experiments confirmed the finding that pentobarbital interferes with the expression of morphine tolerance in rats that had not previously received barbiturate-opiate pairings. In addition, the results supported the state-dependency interpretation of this interference: Rats that had pretest administrations of morphine signaled by pentobarbital, as well as the test administration, displayed substantial morphine tolerance. Moreover, if pretest morphine administrations were signaled by pentobarbital, omission of the barbiturate cue on the test session attenuated tolerance.