title: Induction of P-glycoprotein and Bcrp at the rat blood-brain barrier following a subchronic morphine treatment is mediated through NMDA/COX-2 activation.
abstract: Subchronic morphine treatment induces P-glycoprotein (P-gp) up-regulation at the blood-brain barrier. This study investigates the rate and extent to which P-gp and breast cancer-resistance protein (Bcrp) increase at the rat blood-brain barrier following subchronic morphine treatment. Rats were given increasing doses of morphine (10-40 mg/kg) or saline i.p. twice daily for 5 days. The brain cortex large vessels and microvessels were then mechanical isolated 6, 9, 12, 24, and 36 h after the last injection. The gene and protein expression of P-gp and Bcrp in morphine-treated and control rats were compared by qRT-PCR and western blotting. The levels of Mdr1a and Bcrp mRNAs were not significantly modified 6 h post morphine, but the Mdr1a mRNA increased 1.4-fold and Bcrp mRNA 2.4-fold at 24 h. P-gp and Bcrp protein expression in brain microvessels was unchanged 6 h post morphine and increased 1.5-fold at 24 h. This effect was more pronounced in large vessels than in microvessels. However, extracellular morphine concentrations of 0.01-10 μM did not modify the expressions of the MDR1 and BCRP genes in hCMEC/D3 human endothelial brain cells in vitro. MK-801 (NMDA antagonist) and meloxicam (cyclo-oxygenase-2 inhibitor) given after morphine treatment completely blocked P-gp and Bcrp up-regulation. Interestingly, misoprostol and iloprost, two well-known agonists of prostaglandin E2 receptors induced both MDR1 and BCRP mRNA levels in hCMEC/D3. Thus, morphine does not directly stimulate P-gp and Bcrp expression by the brain endothelium, but glutamate released during morphine withdrawal may do so by activating the NMDA/cyclo-oxygenase-2 cascade.
authors: CNRS, UMR 8206, Neuropsychopharmacologie des addictions, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France.
authors: Salah
authors: S
authors: Yousif
authors: Catarina
authors: C
authors: Chaves
authors: Sophie
authors: S
authors: Potin
authors: Isabelle
authors: I
authors: Margaill
authors: Jean-Michel
authors: JM
authors: Scherrmann
authors: Xavier
authors: X
authors: Declèves
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000033:anatomy & histology; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D008297:Male; D000077239:Meloxicam; D016595:Misoprostol / Q000494:pharmacology; D009020:Morphine / Q000008:administration & dosage*; D016202:N-Methylaspartate / Q000378:metabolism*; D009294:Narcotics / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D016861:Cyclooxygenase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009294:Narcotics; D012333:RNA, Messenger; D013843:Thiazines; D013844:Thiazoles; D016595:Misoprostol; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D009020:Morphine; C095122:multidrug resistance protein 3; D051546:Cyclooxygenase 2; D016285:Iloprost; D000077239:Meloxicam