THE EFFECT OF MELANOTROPHIN RELEASE INHIBITING FACTOR (MIF) AND CYCLO (LEU‐GLY) ON THE TOLERANCE TO MORPHINE‐INDUCED ANTINOCICEPTION IN THE RAT: A DOSE‐RESPONSE STUDY

Abstract

1 The effects of melanotrophin release inhibiting factor (MIF) and its cyclic analogue cyclo (Leu-Gly) on tolerance to the analgesic effect of morphine were studied in male Sprague-Dawley rats. 2 Tolerance to morphine was induced by implantation of four morphine pellets (each containing 75 mg of morphine free base) during a 3 day period. 3 Daily subcutaneous administration of MIF and cyclo (Leu-Gly) before and during the morphine pellet implantation inhibited the development of tolerance to morphine analgesia. The minimum daily dose of the peptides required to produce a significant effect was 0.5 mg/kg. 4 The effects of single injections of MIF and cyclo (Leu-Gly) on morphine tolerance revealed that the minimum doses of cyclo (Leu-Gly) and MIF to inhibit morphine tolerance were 4 and 8 mg/kg, respectively. 5 Chronic treatment with morphine resulted in an enhanced hypothermic response to a dopamine agonist, apomorphine. The enhancement of this response was blocked by both MIF and cyclo (Leu-Gly) in doses that inhibited morphine tolerance. 6 It is concluded that MIF and cyclo (Leu-Gly) block the development of analgesic tolerance as well as dopamine receptor hypersensitivity induced by chronic morphine treatment and the two phenomena may be interrelated.