Effect of Cyproheptadine on Morphine Analgesia, Tolerance and Dependence

The effect of cyproheptadine on morphine induced analgesia, tolerance and dependence was investigated in mice and rats. Analgesia was estimated by hot plate method. Pretreatment of mice with cyproheptadine (10 mg/kg s.c.) did not alter the ED50 of morphine analgesia, however, tolerance to the analgesic effect of morphine was reduced by cyproheptadine. Daily subcutaneous injection of morphine was reduced by cyproheptadine. Daily subcutaneous injection of morphine for one week significantly increased the ED50 of morphine from 3 (4.1-2.2) on first day of treatment to 6.68 (9.49-4.7) mg/kg on sixth day of treatment. However, daily co-administration of cyproheptadine significantly reduced the ED50 of morphine after 6 days of treatment to 5.1 (6.73-3.86) mg/kg. The effect of cyproheptadine on abstinence signs precipitated by naloxone in morphine dependent rats was examined. Dependence was produced by two daily s.c. injection of morphine starting with 2.5 mg/kg and doubling the dose each day up to a maximum of 40 mg/kg. The with drawl signs that were observed and recorded were umpping, teeth chattering, weight loss, wet dog shakes, diarrhea, ptosis, rhinorrhea and urination and wet dog shakes. However, jumping, teeth chattering, rhinorrhea and ptosis were not significantly affected by cyproheptadine. We conclude from these results that 5-HT plays a minor role in analgesia while 5-HT seems to partly contribute to the tolerance to and dependence on morphine.