Previous research has shown that brief and intermittent activity wheel running attenuates conditioned place preference (CPP) to morphine in rats, which suggests that exercise may produce a cross-tolerance to opiates. On the other hand, a different exercise paradigm, chronic and voluntary wheel running, enhances learning in contextual conditioning tasks. The present experiments tested CPP to 2.5, 5, and 7.5 mg/kg morphine in sedentary rats and rats provided free access to running wheels for three weeks. Sucrose preference was also tested to determine exercise's influence on appetitive processes. Levels of mRNA encoding brain-derived neurotrophic factor and preprogalanin mRNA were quantified using in situ hybridization. In rats that exhibited CPP to morphine, exercising rats spent significantly more time per entry in the morphine-paired chamber during the CPP test. CPP to morphine was dose-dependent. The expression of hippocampal brain-derived neurotrophic factor (BDNF) was greater in exercising rats compared to the sedentary group. Preprogalanin (GAL) mRNA expression in the locus coeruleus (LC) was positively correlated with mean distance run. These results suggest that while chronic exercise may produce cross-tolerance to opioids, exercise-induced enhancement of associative learning caused by exercise may override this effect in the conditioned place preference procedure.