Luteinizing hormone releasing hormone mediates naloxone's effects on serum luteinizing hormone levels in normal and morphine-sensitized male rats

Theodore J. Cicero, Peter F. Schmoeker, Edward R. Meyer, Brian T. Miller

    Research output: Contribution to journalArticle

    29 Citations (Scopus)

    Abstract

    Naloxone produces large increases in serum luteinizing hormone (LH) levels in normal males and females, supporting a role for endogenous opioids (EOP) in the tonic inhibition of LH. Since the antagonist apparently exerts no important effects on the pituitary, the reasonable assumption has been made that it elevates gonadotropin levels by affecting the release of LH-releasing hormone (LHRH) from the hypothalamus. However, at present there is no direct in vivo evidence supporting this widely-held view. In an attempt to directly demonstrate that naloxone increases the secretion of LHRH, and thereby elevattes serum LH levels, we examined whether a potent synthetic antagonist of LHRH ([D-p Glu1, D-Phe2, D-Trp3,6]-LHRH, GPT-LHRH) blocked the effects of naloxone in male rats with a normal response to naloxone and in those with a markedly enhanced sensitivity to the drug induced by a brief period of morphine pellet implantation. Our results demonstrated that GT-LHRH antagonized equipotent doses of LHRH (100 ng/kg) and naloxone (0.5 mg/kg) over a similar time course with approximately the same AD50. Most importantly, however, we showed that the GPT-LHRH produced equivalent, parallel shifts to the right in the dose-response curves for LHRH and naloxone, indicative of competitive inhibition. We also found that GPT-LHRH completely abolished the enhanced response to naloxone's effects on LH which occurs in morphine-pretreated rats. Since we observed no competition between LHRH and naloxone for their binding sites in pituitary or brain, the only viable interpretation of our results is that naloxone increases LH by inducing the release of LHRH.

    Original languageEnglish (US)
    Pages (from-to)467-474
    Number of pages8
    JournalLife Sciences
    Volume37
    Issue number5
    DOIs
    StatePublished - Aug 5 1985

    Fingerprint

    Naloxone
    Luteinizing Hormone
    Gonadotropin-Releasing Hormone
    Morphine
    Rats
    Serum
    Gonadotropins
    Opioid Analgesics
    Hypothalamus
    Brain
    Binding Sites

    ASJC Scopus subject areas

    • Pharmacology

    Cite this

    Luteinizing hormone releasing hormone mediates naloxone's effects on serum luteinizing hormone levels in normal and morphine-sensitized male rats. / Cicero, Theodore J.; Schmoeker, Peter F.; Meyer, Edward R.; Miller, Brian T.

    In: Life Sciences, Vol. 37, No. 5, 05.08.1985, p. 467-474.

    Research output: Contribution to journalArticle

    Cicero, Theodore J. ; Schmoeker, Peter F. ; Meyer, Edward R. ; Miller, Brian T. / Luteinizing hormone releasing hormone mediates naloxone's effects on serum luteinizing hormone levels in normal and morphine-sensitized male rats. In: Life Sciences. 1985 ; Vol. 37, No. 5. pp. 467-474.
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    abstract = "Naloxone produces large increases in serum luteinizing hormone (LH) levels in normal males and females, supporting a role for endogenous opioids (EOP) in the tonic inhibition of LH. Since the antagonist apparently exerts no important effects on the pituitary, the reasonable assumption has been made that it elevates gonadotropin levels by affecting the release of LH-releasing hormone (LHRH) from the hypothalamus. However, at present there is no direct in vivo evidence supporting this widely-held view. In an attempt to directly demonstrate that naloxone increases the secretion of LHRH, and thereby elevattes serum LH levels, we examined whether a potent synthetic antagonist of LHRH ([D-p Glu1, D-Phe2, D-Trp3,6]-LHRH, GPT-LHRH) blocked the effects of naloxone in male rats with a normal response to naloxone and in those with a markedly enhanced sensitivity to the drug induced by a brief period of morphine pellet implantation. Our results demonstrated that GT-LHRH antagonized equipotent doses of LHRH (100 ng/kg) and naloxone (0.5 mg/kg) over a similar time course with approximately the same AD50. Most importantly, however, we showed that the GPT-LHRH produced equivalent, parallel shifts to the right in the dose-response curves for LHRH and naloxone, indicative of competitive inhibition. We also found that GPT-LHRH completely abolished the enhanced response to naloxone's effects on LH which occurs in morphine-pretreated rats. Since we observed no competition between LHRH and naloxone for their binding sites in pituitary or brain, the only viable interpretation of our results is that naloxone increases LH by inducing the release of LHRH.",
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