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Research ArticleTOXICOLOGY

Repeated Exposures to Heroin and/or Cadmium Alter the Rate of Formation of Morphine Glucuronides in the Rat

Letizia Antonilli, Carmen Suriano, Giovanna Paolone, Aldo Badiani and Paolo Nencini
Journal of Pharmacology and Experimental Therapeutics November 2003, 307 (2) 651-660; DOI: https://doi.org/10.1124/jpet.103.055467
Letizia Antonilli
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Carmen Suriano
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Giovanna Paolone
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Aldo Badiani
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Paolo Nencini
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Abstract

After absorption, heroin is transformed into mono-acetyl-morphine and then into morphine. Morphine, in turn, is metabolized to morphine-3-glucuronide (M3G), an inactive compound, and morphine-6-glucuronide (M6G), a potent opioid agonist. Thus, changes in the rate of formation of M6G may alter the pharmacological consequences of a treatment with heroin or morphine. In this study, we investigate the effect of repeated exposures (10 daily i.p. injections) to heroin, morphine, cadmium (which has been previously shown to inhibit M3G formation in vitro), or heroin + cadmium on morphine glucuronidation both in vivo and ex vivo (i.e., microsomal preparation obtained from rats treated in vivo). Repeated heroin (2.5, 5.0, and 10 mg/kg) increased plasma levels of M6G (which was undetectable in all other groups) and reduced those of M3G. Also, the microsomal preparations obtained from the liver of repeated heroin rats, when incubated with morphine, yielded significant amounts of M6G (which was undetectable in all other groups) and decreased levels of M3G relative to the control groups. These effects were reversible upon discontinuation of heroin administration. In contrast, repeated morphine (10, 20, and 40 mg/kg) only slightly reduced M3G formation at the dose of 40 mg/kg. Repeated cadmium (5, 15, and 45 μg/kg) reduced the rate of M3G formation without inducing M6G synthesis. The effects of the repeated coadministration of heroin (10 mg/kg) and cadmium (15 μg/kg) were virtually identical to those of repeated heroin alone. In summary, repeated exposure of rats to heroin can shift morphine glucuronidation toward the formation of the active metabolite M6G.

Footnotes

  • This study was supported by grants from the Ministry of University and of Scientific and Technological Research of Italy (Finanziamenti COFIN) and from the University of Rome “La Sapienza” (Finanziamenti per Ricerche d'Ateneo).

  • DOI: 10.1124/jpet.103.055467.

  • ABBREVIATIONS: 6-MAM, 6-monoacethylmorphine; M3G, morphine-3-glucuronide; M6G, morphine-6-glucuronide; UGT, UDP-glucuronosyltransferase; UDPGA, uridinediphosphoglucuronic acid; HPLC, high-performance liquid chromatography.

    • Received June 18, 2003.
    • Accepted August 7, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 307 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 307, Issue 2
1 Nov 2003
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Research ArticleTOXICOLOGY

Repeated Exposures to Heroin and/or Cadmium Alter the Rate of Formation of Morphine Glucuronides in the Rat

Letizia Antonilli, Carmen Suriano, Giovanna Paolone, Aldo Badiani and Paolo Nencini
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 651-660; DOI: https://doi.org/10.1124/jpet.103.055467

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Research ArticleTOXICOLOGY

Repeated Exposures to Heroin and/or Cadmium Alter the Rate of Formation of Morphine Glucuronides in the Rat

Letizia Antonilli, Carmen Suriano, Giovanna Paolone, Aldo Badiani and Paolo Nencini
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 651-660; DOI: https://doi.org/10.1124/jpet.103.055467
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