Possible involvement of endogenous opiates in the tolerance to the anorectic effect of fenfluramine.
Repeated administration of fenfluramine leads to a rapid and progressive loss of its effectiveness in reducing food intake. The animals tolerant to the anorectic effect of fenfluramine had markedly low basal hypothalamic serotonin (5-HT) levels. In this brain area the levels of [Met5]enkephalin-like immunoreactive material were, on the contrary, significantly higher in fenfluramine-tolerant animals than in controls. In tolerant animals the drug failed to further decrease 5-HT concentrations unless it was given at doses also reducing food intake. On the other hand, in acute experiments, morphine pretreatment potentiated and naloxone antagonized fenfluramine-induced depletion of striatal and hypothalamic 5-HT stores. In addition, when given to fenfluramine-tolerant rats, morphine restored the efficacy of the anorectic agent. After morphine pretreatment, fenfluramine depleted 5-HT and reduced food intake in tolerant animals. These findings, while further substantiating the importance of 5-HT in mediating fenfluramine anorexia, also suggest that endogenous opiates may play an important role in the processes through which tolerance to this drug develops. Fenfluramine reduces food intake by releasing 5-HT and tolerance to its anorectic effect would be a consequence of an inability to further release 5-HT. However, because release of 5-HT by fenfluramine seems to be modulated by opiates, repeated administration of fenfluramine might alter such modulatory mechanisms and tolerance to the effects of the drug would develop.
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D004361:Drug Tolerance; D004435:Eating / Q000187:drug effects; D004723:Endorphins / Q000502:physiology*; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives / Q000378:metabolism; D005277:Fenfluramine / Q000494:pharmacology*; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D011292:Premedication; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism / Q000502:physiology
D001067:Appetite Depressants; D004723:Endorphins; C024693:enkephalin-Met, like substances; D005277:Fenfluramine; D012701:Serotonin; D009270:Naloxone; D004744:Enkephalin, Methionine; D009020:Morphine