INHIBITION OF TOLERANCE TO THE PHARMACOLOGICAL EFFECTS OF HUMAN BETA-ENDORPHIN BY PROLYL-LEUCYL-GLYCINAMIDE AND CYCLO(LEUCYLGLYCINE) IN THE RAT

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  • 1 January 1981
    • journal article
    • research article
    • Vol. 218  (2) , 404-408
Abstract
Acute intraventricular administration of human .beta.-endorphin (15 .mu.g) produced analgesia, hypothermia and catalepsy in male Sprague-Dawley rats. Injections of .beta.-endorphin given every 8 h for 3 days resulted in the development of tolerance to all of the above mentioned pharmacological effects. Tolerance developed rapidly to the hypothermic effect and less rapidly to the analgesic and cataleptic effects. After the 3rd or the 4th injection of .beta.-endorphin, pronounced hyperthermia, rather than hypothermia, was observed. After 7 or 8 injections of .beta.-endorphin, tolerance to the analgesic effect was complete and the cataleptic effect was reduced to 50% of the original. Daily s.c. administration of Pro-Leu-Gly-NH2 (MIF, melanotropin release inhibiting factor) or cyclo(Leu-Gly) (2 mg/kg each) blocked the development of tolerance to the analgesic and cataleptic effects of .beta.-endorphin. The hyperthermic effect of .beta.-endorphin in .beta.-endorphin tolerant rats was partially blocked by both MIF and cyclo(Leu-Gly). Multiple injections of MIF or cyclo(Leu-Gly) did not alter .beta.-endorphin-induced analgesia, catalepsy and hypothermia in rats which were given repeated intraventricular injections of saline. Since MIF is a naturally occurring peptide of hypothalamic origin, the hypothalamus may be an important site in regulating the pharmacological effects of chronically administered endogenous opiates.