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Possible involvement of endogenous opiates in the tolerance to the anorectic effect of fenfluramine.
J Pharmacol Exp Ther. 1984 Feb; 228(2):446-53.JP

Abstract

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.

Authors

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Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

6694120

Citation

Groppetti, A, et al. "Possible Involvement of Endogenous Opiates in the Tolerance to the Anorectic Effect of Fenfluramine." The Journal of Pharmacology and Experimental Therapeutics, vol. 228, no. 2, 1984, pp. 446-53.
Groppetti A, Parenti M, Dellavedova L, et al. Possible involvement of endogenous opiates in the tolerance to the anorectic effect of fenfluramine. J Pharmacol Exp Ther. 1984;228(2):446-53.
Groppetti, A., Parenti, M., Dellavedova, L., & Tirone, F. (1984). Possible involvement of endogenous opiates in the tolerance to the anorectic effect of fenfluramine. The Journal of Pharmacology and Experimental Therapeutics, 228(2), 446-53.
Groppetti A, et al. Possible Involvement of Endogenous Opiates in the Tolerance to the Anorectic Effect of Fenfluramine. J Pharmacol Exp Ther. 1984;228(2):446-53. PubMed PMID: 6694120.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Possible involvement of endogenous opiates in the tolerance to the anorectic effect of fenfluramine. AU - Groppetti,A, AU - Parenti,M, AU - Dellavedova,L, AU - Tirone,F, PY - 1984/2/1/pubmed PY - 1984/2/1/medline PY - 1984/2/1/entrez SP - 446 EP - 53 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 228 IS - 2 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/6694120/Possible_involvement_of_endogenous_opiates_in_the_tolerance_to_the_anorectic_effect_of_fenfluramine_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=6694120 DB - PRIME DP - Unbound Medicine ER -