TO evaluate the molecular mechanisms that mediate the effect of learning on morphine tolerance in rats, we examined striatal c-Fos, and c-Jun protein expression, and AP-1 DNA binding. Morphine paired with a conditioned stimulus (CS) led to analgesic tolerance in the presence of the CS. Rats receiving morphine unpaired with the CS displayed significantly less tolerance than paired morphine animals. Striatal c-Fos protein levels and AP-1 DNA binding activity were increased in rats receiving paired morphine compared with rats that did not receive morphine but not in rats receiving morphine without the CS. No differences were found in c-Jun levels. These results suggest that Pavlovian conditioning may account, in part, for the molecular mechanisms associated with morphine tolerance.