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Induction of P-glycoprotein and Bcrp at the rat blood-brain barrier following a subchronic morphine treatment is mediated through NMDA/COX-2 activation.

J Neurochem. 2012 Jul 28;

Authors: Yousif S, Chaves C, Potin S, Scherrmann JM, Declèves X


Subchronic morphine treatment induces P-glycoprotein (P-gp) up-regulation at the blood-brain barrier (BBB). This study investigates the rate and extent to which P-gp and Bcrp increase at the rat BBB 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 6h 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 (COX-2 inhibitor) given after morphine treatment completely blocked P-gp and Bcrp up-regulation. Interestingly, misoprostol and iloprost, two well known agonists of PGE2 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/COX-2 cascade. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

PMID: 22845665 [PubMed - as supplied by publisher]