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Research ArticleArticle

Morphine-6β-Glucuronide-Induced Hyperphagia: Characterization of Opioid Action By Selective Antagonists and Antisense Mapping in Rats

Liza Leventhal, Robert M. Silva, Grace C. Rossi, Gavril W. Pasternak and Richard J. Bodnar
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 538-544;
Liza Leventhal
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Robert M. Silva
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Grace C. Rossi
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Gavril W. Pasternak
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Richard J. Bodnar
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Abstract

Opiate drugs such as morphine stimulate food intake in rats. The morphine metabolite, morphine-6β-glucuronide (M6G), is more active than morphine in analgesic assays, and appears to act through distinct receptors. Thus, although morphine analgesia is decreased by antisense oligodeoxynucleotides (AS ODNs) targeting exons 1 and 4 of the MOR-1 clone, M6G analgesia is reduced by probes targeting exons 2 and 3 of the MOR-1 clone. Our study examined whether central administration of M6G increased food intake in rats, and characterized this response using either selective mu, kappa1,delta1 and delta2antagonists, or antisense directed against the various cloned opioid receptors. Central M6G (10–1000 ng) significantly and dose-dependently increased intake after 4 hr. Whereas mu antagonism with βFNA significantly and dose-dependently reduced M6G-induced hyperphagia, equimolar doses of delta1,delta2, and kappa1antagonists were ineffective. AS ODNs directed against either exons 2 or 3 of the MOR-1 clone blocked M6G-induced hyperphagia, whereas either AS ODNs directed against exons 1 or 4, or a MS ODN directed against exon 2 were ineffective. In contrast, an AS ODN probe directed against exon 1, but not exon 2, of the MOR-1 clone reduced morphine-induced hyperphagia, an effect identical to DAMGO-induced hyperphagia. Whereas M6G-induced hyperphagia was insensitive to antisense probes directed against the DOR-1, KOR-1 and KOR-3/ORL1 clones, these probes respectively reduced hyperphagia induced by deltorphin II, U50488H and nociceptin. Although pharmacological data indicate that M6G-induced hyperphagia acts through mu receptors, antisense data imply that the hyperphagic actions of M6G are mediated by a receptor distinct from traditional mu agonists, either as an alternative splice variant of the MOR-1 clone or a distinct gene.

Footnotes

  • Send reprint requests to: Dr. R. J. Bodnar, Department of Psychology, Queens College, CUNY, 65-30 Kissena Blvd., Flushing, NY 11367.

  • This work was supported in part by NIDA Grants DA05746 (L.L.), DA04194 (R.J.B.), DA07274 (G.W.P.), DA00220 (G.W.P.) and DA00310 (G.C.R.).

  • Abbreviations:
    AS ODN
    antisense oligodeoxynucleotides
    β-FNA
    β-funaltrexamine
    CON
    control
    DALCE
    [d-Ala2, Leu5, Cys6]-enkephalin
    DAMGO
    [d-Ala2, MePhe4, Gly-ol5]-enkephalin
    Delt II
    deltorphin II
    icv
    intracerebroventricular
    KOR-1
    kappaopioid receptor clone
    KOR-3/ORL1
    kappa−3-like opioid receptor clone
    M6G
    morphine-6β-glucuronide
    MOR-1
    mu opioid receptor clone
    MS ODN
    missense oligodeoxynucleotide
    NTII
    naltrindole isothiocyanate
    NBNI
    nor-binaltorphamine
    • Received August 21, 1998.
    • Accepted June 22, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

Morphine-6β-Glucuronide-Induced Hyperphagia: Characterization of Opioid Action By Selective Antagonists and Antisense Mapping in Rats

Liza Leventhal, Robert M. Silva, Grace C. Rossi, Gavril W. Pasternak and Richard J. Bodnar
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 538-544;

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Research ArticleArticle

Morphine-6β-Glucuronide-Induced Hyperphagia: Characterization of Opioid Action By Selective Antagonists and Antisense Mapping in Rats

Liza Leventhal, Robert M. Silva, Grace C. Rossi, Gavril W. Pasternak and Richard J. Bodnar
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 538-544;
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