The role of metabolism in the action of prolyl-leucyl-glycinamide on the development of tolerance to the analgesic effect of morphine.

Administration of melanotropin release inhibiting factor, a tripeptide (Pro-Leu-Gly-NH2) has been shown to inhibit the development of tolerance to opiates. In order to understand the mechanism by which this effect is produced, the effects of the possible metabolites of Pro-Leu-Gly-NH2 on the development of tolerance to the analgesic effects of morphine were determined in male Sprague-Dawley rats. Rats were made tolerant to morphine by the subcutaneous implantation of four pellets of morphine over a 3-day period. Each pellet contained 75 mg of morphine, free base. Rats serving as controls were implanted with placebo pellets. Following implantation of the morphine-containing pellets, tolerance developed to the analgesic effect of morphine as shown by the decreased response to morphine. Subcutaneous injections of Pro-Leu-Gly-NH2, Pro-Leu-OH or Leu-Gly-NH2 (10 mumol/kg per day), prior to and during the implantation of pellets, inhibited the development of tolerance to morphine. However, Pro-Leu-Gly-OH and Leu-Gly-OH, administered in the same dose as the other compounds, had no effect on the development of tolerance to the analgesic effect of morphine. It is concluded that the inhibitory effect of Pro-Leu-Gly-NH2, which has a short biological half life, may be mediated by its conversion to active metabolites.