title: Morphine induces expression of platelet-derived growth factor in human brain microvascular endothelial cells: implication for vascular permeability.
abstract: Despite the advent of antiretroviral therapy, complications of HIV-1 infection with concurrent drug abuse are an emerging problem. Morphine, often abused by HIV-infected patients, is known to accelerate neuroinflammation associated with HIV-1 infection. Detailed molecular mechanisms of morphine action however, remain poorly understood. Platelet-derived growth factor (PDGF) has been implicated in a number of pathological conditions, primarily due to its potent mitogenic and permeability effects. Whether morphine exposure results in enhanced vascular permeability in brain endothelial cells, likely via induction of PDGF, remains to be established. In the present study, we demonstrated morphine-mediated induction of PDGF-BB in human brain microvascular endothelial cells, an effect that was abrogated by the opioid receptor antagonist-naltrexone. Pharmacological blockade (cell signaling) and loss-of-function (Egr-1) approaches demonstrated the role of mitogen-activated protein kinases (MAPKs), PI3K/Akt and the downstream transcription factor Egr-1 respectively, in morphine-mediated induction of PDGF-BB. Functional significance of increased PDGF-BB manifested as increased breach of the endothelial barrier as evidenced by decreased expression of the tight junction protein ZO-1 in an in vitro model system. Understanding the regulation of PDGF expression may provide insights into the development of potential therapeutic targets for intervention of morphine-mediated neuroinflammation.
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors: Hongxiu
authors: H
authors: Wen
authors: Yaman
authors: Y
authors: Lu
authors: Honghong
authors: H
authors: Yao
authors: Shilpa
authors: S
authors: Buch
mesh_terms: D000077214:Becaplermin; D015153:Blotting, Western; D001921:Brain / Q000166:cytology*; D002199:Capillary Permeability / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D009020:Morphine / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020574:Proto-Oncogene Proteins c-sis
chemical_list: D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D009020:Morphine