1. The repeated administration of single dose of morphine (10 mg/kg) at 3 to 4 day-intervals caused sensitization to its ambulation-increasing effect.2. The same treatment with caffeine (1, 3 and 10 mg/kg) did not change the effect of caffeine itself, but tended to reduce the sensitivity to morphine.3. Combination of morphine with caffeine enhanced the effect in the 1st administration, though the mice given such combination showed almost the same activity during the repeated administration, and the sensitivity similar to the saline control or drug-naive mice to challenge morphine.4. The ambulation increases caused by morphine (10 mg/kg), caffeine (10 mg/kg) and their combination were reduced by SCH 23390 (0.01 mg/kg), YM-09151-2 (0.01 mg/kg), reserpine (1 mg/kg), α-methyl-p-tyrosine (200 mg/kg), naloxone (1 mg/kg) and N 6 -(L-phenylisopropyl)-adenosine (0.2 mg/kg), although the inhibitory actions were different dependent on the drug conditions.5. The present results indicate complex interactions between morphine and caffeine; enhancement of the acute stimulant effect by the combined administration, but inhibition of morphine sensitization by caffeine, probably through dopaminergic, opioid and adenosinergic systems.