Morphine regulates gene expression of alpha- and beta-chemokines and their receptors on astroglial cells via the opioid mu receptor.
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.
Mahajan
Supriya D
SD
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.
Schwartz
Stanley A
SA
Shanahan
Thomas C
TC
Chawda
Ram P
RP
Nair
Madhavan P N
MP
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
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