Structure activity relationship studies with hypothalamic peptide hormones III. Effect of melanotropin-release inhibiting factor and analogs on tolerance to morphine in the rat

The effects of several analogs of melanotropin-release inhibiting factor (MIF, Pro-Leu-Gly-NH2) on the development of tolerance to the hyperthermic, hypothermic and cataleptic actions of morphine were investigated in male Sprague-Dawley rats. The analogs that were examined included. Pro-Gly-Gly-NH2 (I), Pro-VAl-Gly-NH2 (II), Pro-Leu-beta-Ala-NH2 (III), Pro-Leu-Gly-NHCH3 (IV), Pro-Leu-NH2 (V) and cyclo (Pro-Gly) (VI). Subcutaneous implantation of four morphine pellets (each containing 75 mg of morphine free base) during a 3-day period was used to develop tolerance to the pharmacological effects of morphine. Concurrent daily subcutaneous administration of any of the above peptides (I through VI) at a 10 mu mol/kg dose did not modify the development of tolerance to morphine-induced hyperthermia, hypothermia or catalepsy. The development of tolerance to morphine was, however, inhibited by equivalent doses of MIF. Treatment with these peptides did not alter the distribution of morphine in brain and plasma. It is concluded that the structural requirements for the inhibitory effect of MIF on the development of tolerance to morphine are very strict and that the following modifications in the structure of MIF result in the loss of activity (a) substitution of Gly or Val in place of Leu (b) replacement of Gly-NH2 with Gly-NHCH3 or beta-Ala-NH2 (c) removal of Gly, and (d) removal of Leu followed by cyclization of Pro-Gly.