The rewarding effect of wheel running is hypothesized to be mediated by endogenous opioids. Thus, prior experience with wheel running might be expected to affect the reward value of an opiate drug like morphine. In three similar experiments to test this idea, 10 rats (wheel-morphine group) were confined in running wheels for 2 h on each of eight consecutive days during the first phase; the 10 in the cage-morphine group were confined in small metal cages. Then, in the second phase, a distinctive place was paired with morphine (1 mg/kg) on three occasions to produce conditioned place preference (CPP). In all experiments, CPP occurred in the cage-morphine group, but not in the wheel-morphine group, implying that prior wheel running resulted in cross-tolerance to the rewarding effect of morphine. This finding supports the idea that the rewarding effect of wheel running is mediated by endogenous opioids.