Interactions of opioids with caffeine: evaluation by ambulatory activity in mice.

— Morphine (up to 10 mg kg−1), buprenorphine (up to 0·1 mg kg−1), pentazocine (30 mg kg−1) and caffeine (up to 10 mg kg−1), significantly increased mouse ambulation. The combination of morphine, buprenorphine and pentazocine with caffeine generally enhanced the effect. Dopamine D1- and D2-receptor bockade, depletion of stored dopamine, and inhibition of dopamine synthesis could reduce the ambulation increased by single administration of morphine, buprenorphine and caffeine, and by combined administration of morphine and buprenorphine with caffeine. Although naloxone (0·1–3 mg kg−1) itself did not change mouse ambulation, at 3 mg kg−1, it reduced the effect of caffeine. The repeated administration of morphine (10 mg kg−1) induced a sensitization to the ambulation-increasing effect, and was inhibited by the combination of caffeine (10 mg kg−1) in the repeated administration schedule. The repeated administration of caffeine (10 mg kg−1) with buprenorphine (0·3 mg kg−1) resulted in a decrease in the effect to the level of caffeine alone. The development of cross-sensitization to morphine (10 mg kg−1) by the repeated treatment with buprenorphine (0·3 mg kg−1) was inhibited by caffeine (10 mg kg−1). Our results suggest that the dopaminergic systems are involved in the enhanced interaction of opioids having agonistic action on μ- or σ-receptors with caffeine. However, it is also considered that, following the repeated administration, caffeine acts to reduce the sensitivity to the ambulation-increasing effect of opioids, probably inducing up-regulation of adenosinergic systems.