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Impact of P-glycoprotein at the blood-brain barrier on the uptake of heroin and its main metabolites: behavioral effects and consequences on the transcriptional responses and reinforcing properties

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Abstract

Rationale

Transport across the BBB is a determinant of the rate and extent of drug distribution in the brain. Heroin exerts its effects through its principal metabolites 6-monoacetyl-morphine (6-MAM) and morphine. Morphine is a known substrate of P-glycoprotein (P-gp) at the blood-brain-barrier (BBB) however, little is known about the interaction of heroin and 6-MAM with P-gp.

Objective

The objective of this paper is to study the role of the P-gp-mediated efflux at the BBB in the behavioral and molecular effects of heroin and morphine.

Methods

The transport rates of heroin and its main metabolites, at the BBB, were measured in mice by in situ brain perfusion. We then examined the effect of inhibition of P-gp on the acute nociception, locomotor activity, and gene expression modulations induced by heroin and morphine. The effect of P-gp inhibition during the acquisition of morphine-induced place preference was also studied.

Results

Inhibition of P-gp significantly increased the uptake of morphine but not that of heroin nor 6-MAM. Inhibition of P-gp significantly increased morphine-induced acute analgesia and locomotor activity but did not affect the behavioral effects of heroin; in addition, acute transcriptional responses to morphine were selectively modulated in the nucleus accumbens. Increasing morphine uptake by the brain significantly increased its reinforcing properties in the place preference paradigm.

Conclusions

The present study demonstrated that acute inhibition of P-gp not only modulates morphine-induced behavioral effects but also its transcriptional effects and reinforcing properties. This suggests that, in the case of morphine, transport across the BBB is critical for the development of dependence.

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Abbreviations

P-gp:

P-glycoprotein

6-MAM:

6-Monoacetyl-morphine

Nac:

Nucleus accumbens

IEG:

Immediate early genes

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Acknowledgments

The authors thank Didier Fauconnier for technical assistance and the animal facility of the Institut Medicament-Toxicologie-Chimie-Environnement for providing resources. This work was supported by Centre National de la Recherche Scientifique (CNRS) UMR8206 and Institut National de la Santé et de la Recherche Médicale (INSERM) U705 and Université Paris Descartes. The authors have no financial interest to disclose.

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Authors and Affiliations

  1. Laboratoire de Neuropsychopharmacologie des Addictions Centre National de la Recherche Scientifique Unité Mixte de Recherche 8206, 4 avenue de l’Observatoire, 75006, Paris, France

    Marianne Seleman, Hélène Chapy, Salvatore Cisternino, Cindie Courtin, Maria Smirnova, Jean-Michel Scherrmann, Florence Noble & Cynthia Marie-Claire

  2. Institut National de la Santé et de la Recherche Médicale, U 705, Paris, France

    Marianne Seleman, Hélène Chapy, Salvatore Cisternino, Cindie Courtin, Maria Smirnova, Jean-Michel Scherrmann, Florence Noble & Cynthia Marie-Claire

  3. Sorbonne Paris Cité, Faculté de Pharmacie, Université Paris Descartes, 4 avenue de l’Observatoire, 75006, Paris, France

    Marianne Seleman, Hélène Chapy, Salvatore Cisternino, Cindie Courtin, Maria Smirnova, Jean-Michel Scherrmann, Florence Noble & Cynthia Marie-Claire

  4. Hôpital Jean Verdier—AP-HP—Laboratoire de Toxicologie, 93140, Bondy, Paris, France

    Joël Schlatter & Fouad Chiadmi

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  1. Marianne Seleman
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  2. Hélène Chapy
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  3. Salvatore Cisternino
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  9. Florence Noble
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  10. Cynthia Marie-Claire
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Correspondence to Florence Noble.

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Seleman, M., Chapy, H., Cisternino, S. et al. Impact of P-glycoprotein at the blood-brain barrier on the uptake of heroin and its main metabolites: behavioral effects and consequences on the transcriptional responses and reinforcing properties. Psychopharmacology 231, 3139–3149 (2014). https://doi.org/10.1007/s00213-014-3490-9

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  • DOI: https://doi.org/10.1007/s00213-014-3490-9

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