title: Morphine regulates gene expression of alpha- and beta-chemokines and their receptors on astroglial cells via the opioid mu receptor.
abstract: The brain is a target organ for recreational drugs and HIV-1. Epidemiological data demonstrate that opioid abuse is a risk factor for HIV-1 infection and progression to AIDS. Chemokines and their receptors have been implicated in the neuropathogenesis of HIV-1 infections. However, little is known about the effects of opioids on the expression of chemokines and their receptors (the latter also are HIV-1 coreceptors) by cells of the CNS. Herein we describe the effects of morphine on gene expression of the alpha- and beta-chemokines and their receptors by the astrocytoma cell line U87 and by primary normal human astrocyte (NHA) cultures. U87 cells treated with morphine showed significant down-regulation of IL-8 gene expression, whereas expression of the IL-8 receptor CXCR2 was reciprocally up-regulated as detected by RT-PCR. Treatment of NHAs with morphine suppressed IL-8 and macrophage-inflammatory protein-1beta gene expression, whereas expression of their receptor genes, CCR3 and CCR5, was simultaneously enhanced. These morphine-induced effects on U87 and NHA cells were reversed by the opioid mu receptor antagonist beta-funaltrexamine. Morphine also enhanced the constitutive expression of the opioid mu receptor on astroglial cells. Our results support the hypothesis that opioids play a significant role in the susceptibility of the CNS to HIV-1 infection and subsequent encephalopathy by inhibiting local production of HIV-1-protective chemokines (IL-8 and macrophage-inflammatory protein-1beta) and enhancing expression of HIV-1 entry coreceptor genes (CCR3, CCR5, and CXCR2) within the CNS. These effects of opioids appear to be mediated through the opioid mu receptor that we demonstrated on astroglial cells.
authors.affiliation: Department of Medicine, Division of Allergy, Immunology, and Rheumatology, State University of New York and Buffalo General Hospital, Kaleida Health System, Buffalo, NY 14203, USA.
authors.forename: Supriya D
authors.initials: SD
authors.lastname: Mahajan
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Schwartz
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Shanahan
authors.forename: Ram P
authors.initials: RP
authors.lastname: Chawda
authors.forename: Madhavan P N
authors.initials: MP
authors.lastname: Nair
mesh_terms: D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism*; D001254:Astrocytoma / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics*; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D009020:Morphine / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000235:genetics; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics*; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C515350:CCR3 protein, human; D054407:Chemokine CCL4; D019742:Chemokines, CC; D019743:Chemokines, CXC; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D023063:Receptors, Interleukin-8B; D017450:Receptors, Opioid, mu; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine