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Research ArticleDrug Discovery and Translational Medicine

Selective Effects of a Morphine Conjugate Vaccine on Heroin and Metabolite Distribution and Heroin-Induced Behaviors in Rats

M.D. Raleigh, M. Pravetoni, A.C. Harris, A.K. Birnbaum and P.R. Pentel
Journal of Pharmacology and Experimental Therapeutics February 2013, 344 (2) 397-406; DOI: https://doi.org/10.1124/jpet.112.201194
M.D. Raleigh
Departments of Pharmacology (M.D.R., M.P., P.R.P.) and Medicine (M.P., A.C.H., P.R.P.), Medical School, University of Minnesota, Minneapolis Medical Research Foundation (M.P., A.C.H., P.R.P.), and Department of Experimental and Clinical Pharmacology (A.K.B.), College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
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M. Pravetoni
Departments of Pharmacology (M.D.R., M.P., P.R.P.) and Medicine (M.P., A.C.H., P.R.P.), Medical School, University of Minnesota, Minneapolis Medical Research Foundation (M.P., A.C.H., P.R.P.), and Department of Experimental and Clinical Pharmacology (A.K.B.), College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
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A.C. Harris
Departments of Pharmacology (M.D.R., M.P., P.R.P.) and Medicine (M.P., A.C.H., P.R.P.), Medical School, University of Minnesota, Minneapolis Medical Research Foundation (M.P., A.C.H., P.R.P.), and Department of Experimental and Clinical Pharmacology (A.K.B.), College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
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A.K. Birnbaum
Departments of Pharmacology (M.D.R., M.P., P.R.P.) and Medicine (M.P., A.C.H., P.R.P.), Medical School, University of Minnesota, Minneapolis Medical Research Foundation (M.P., A.C.H., P.R.P.), and Department of Experimental and Clinical Pharmacology (A.K.B.), College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
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P.R. Pentel
Departments of Pharmacology (M.D.R., M.P., P.R.P.) and Medicine (M.P., A.C.H., P.R.P.), Medical School, University of Minnesota, Minneapolis Medical Research Foundation (M.P., A.C.H., P.R.P.), and Department of Experimental and Clinical Pharmacology (A.K.B.), College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
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Abstract

Morphine conjugate vaccines have effectively reduced behavioral effects of heroin in rodents and primates. To better understand how these effects are mediated, heroin and metabolite distribution studies were performed in rats in the presence and absence of vaccination. In non-vaccinated rats 6-monoacetylmorphine (6-MAM) was the predominant opioid in plasma and brain as early as 1 minute after i.v. administration of heroin and for up to 14 minutes. Vaccination with morphine conjugated to keyhole limpet hemocyanin (M-KLH) elicited high titers and concentrations of antibodies with high affinity for heroin, 6-MAM, and morphine. Four minutes after heroin administration vaccinated rats showed substantial retention of all three opioids in plasma compared to controls and reduced 6-MAM and morphine, but not heroin, distribution to brain. Administration of 6-MAM rather than heroin in M-KLH vaccinated rats showed a similar drug distribution pattern. Vaccination reduced heroin-induced analgesia and blocked heroin-induced locomotor activity throughout 2 weeks of repeated testing. Higher serum opioid-specific antibody concentrations were associated with higher plasma opioid concentrations, lower brain 6-MAM and morphine concentrations, and lower heroin-induced locomotor activity. Serum antibody concentrations over 0.2 mg/ml were associated with substantial effects on these measures. These data support a critical role for 6-MAM in mediating the early effects of i.v. heroin and suggest that reducing 6-MAM concentration in brain is essential to the efficacy of morphine conjugate vaccines.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA026300, DA030715, and T32-DA07097].

  • dx.doi.org/10.1124/jpet.112.201194.

  • Received October 18, 2012.
  • Accepted December 6, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 2
1 Feb 2013
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Research ArticleDrug Discovery and Translational Medicine

Opioid Vaccine Effects on Heroin Distribution and Behavior

M.D. Raleigh, M. Pravetoni, A.C. Harris, A.K. Birnbaum and P.R. Pentel
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 397-406; DOI: https://doi.org/10.1124/jpet.112.201194

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Research ArticleDrug Discovery and Translational Medicine

Opioid Vaccine Effects on Heroin Distribution and Behavior

M.D. Raleigh, M. Pravetoni, A.C. Harris, A.K. Birnbaum and P.R. Pentel
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 397-406; DOI: https://doi.org/10.1124/jpet.112.201194
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