期刊
PSYCHOPHARMACOLOGY
卷 231, 期 16, 页码 3139-3149出版社
SPRINGER
DOI: 10.1007/s00213-014-3490-9
关键词
Morphine; Heroin; P-glycoprotein; Gene expression; Nociception; Locomotor activity
资金
- Centre National de la Recherche Scientifique (CNRS) [UMR8206]
- Institut National de la Sante et de la Recherche Medicale (INSERM) [U705]
- Universite Paris Descartes
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. 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. 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. 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. 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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