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.