Effects of Caffeine on Morphine Tolerance and Analgesia in Mice

Caffeine, an adenosine A1, A2A, and A2B receptor antagonist, is frequently used as an adjuvant analgesic in combination with non steroidal anti-inflammatory drugs or opioids. The aim of this study was to evaluate the effects of caffeine on preventing the development of morphine tolerance and analgesia in mice. In this study, different groups of mice received morphine (30 mg/kg) + saline (10 ml/kg), or morphine (30 mg/kg) + caffeine (10, 15, 25, 50, 75, or 100 mg/kg) i.p. once a day for four days. Tolerance was assessed by administration of morphine (9 mg/kg) and using hot-plate test on the fifth day. Analgesic effects of caffeine also were evaluated alone or in combination with different doses of morphine. It was found that pretreatment with caffeine (75, 100 mg/kg) decreased the degree of morphine tolerance significantly (p<0.01). Combination of caffeine (10, 50 mg/kg) with morphine (3, 6, 9 mg/kg) caused a significant decrease in morphine analgesic effect (p<0.01). But, in high doses of caffeine (100 mg/kg) the analgesic effect of morphine increased significantly (p<0.01). This effect was inhibited by atropine (5 mg/kg, SC). These effects can be related to different mechanisms of caffeine in different doses and the effects of caffeine to the release of acetylcholine.