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

Abstract

The effects of melanotropin release inhibiting factor (Pro-Leu-Gly-NH2; MIF) and its three analogs Pro-ILeu-Gly-NHi2, Leu-Gly-NH2 (a metabolite of MIF) and cyclo (Leu-Gly) (an analog derived theoretically from MIF) on tolerance to morphine-induced hyperthermia, hypothermia and catalepsy were studied in male Sprague-Dawley rats. Subcutaneous implantation of four morphine pellets (each containing 75 mg of morphine-free base) during a 3-day period resulted in the development of tolerance to these pharmacological effects of morphine as evidenced by decreased intensity of responses to designated i.p. doses of morphine. Concurrent daily s.c. administration of each peptide, injected 24 hr apart for 3 days, resulted in blockade of tolerance to the pharmacological effects of morphine as evidenced by a greater pharmacological response in peptide plus morphine-treated rats as compared with the vehicle plus morphine-treated rats. Multiple injections of peptides did not modify morphine-induced responses in rats implanted with placebo pellets. The blockade of tolerance to morphine by these peptides was not associated with changes in the distribution of morphine in brain and plasma. These studies indicate that the following changes do not modify the inhibitory action of MIF tolerance: 1) substitution of ILeu in place of Leu in MIF; 2) cleavage of the Pro-Leu bond which gives rise to Leu-Gly-NH2; and 3) possible cyclization (diketopiperazine formation) of Leu-Gly-NH2 which yields cyclo (Leu-Gly), and that linear and cyclic peptides either derived from the hypothalamus or synthesized may provide agents to block opiate-induced tolerance.