Methysergide and metergoline reduce morphine analgesia with no effect on the development of tolerance in rats

A single subcutaneous injection of 5 mg/kg metergoline or 10 mg/kg methysergide, two serotonin antagonists, or 1 mg/kg naloxone, significantly reduced the effect of a subcutaneous dose of 3 mg/kg morphine in the tail immersion test in rats. The same drugs and doses were administered concurrently with 10 mg/kg morphine twice daily for 3 days and nociceptive responses were measured 96 h later. Tolerance to the effect of 3 mg/kg morphine was comparable in animals which had received vehicle + morphine or serotonin antagonists + morphine, whereas naloxone completely prevented the development of tolerance. The results argue against a role of serotonin in the development of tolerance to the antinociceptive effect of morphine and suggest it may be possible to dissociate morphine analgesia from tolerance development, at least in the conditions used in the present study.