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.
BACKGROUND
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.
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
M
Seleman
Hélène
H
Chapy
Salvatore
S
Cisternino
Cindie
C
Courtin
Maria
M
Smirnova
Joël
J
Schlatter
Fouad
F
Chiadmi
Jean-Michel
JM
Scherrmann
Florence
F
Noble
Cynthia
C
Marie-Claire
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects*; D003524:Cyclosporins / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D003932:Heroin / Q000378:metabolism*; D006556:Heroin Dependence / Q000523:psychology*; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009022:Morphine Derivatives / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009294:Narcotics / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D009022:Morphine Derivatives; D009294:Narcotics; D003932:Heroin; D009020:Morphine; C026979:6-O-monoacetylmorphine; C070272:valspodar