Morphine and HIV-Tat increase microglial-free radical production and oxidative stress: possible role in cytokine regulation.
Opiate abuse alters the progression of human immunodeficiency virus and may increase the risk of neuroAIDS. As neuroAIDS is associated with altered microglial reactivity, the combined effects of human immunodeficiency virus-Tat and morphine were determined in cultured microglia. Specifically, experiments determined the effects of Tat and morphine on microglial-free radical production and oxidative stress, and on cytokine release. Data show that combined Tat and morphine cause early and synergistic increases in reactive oxygen species, with concomitant increases in protein oxidation. Furthermore, combined Tat and morphine, but not Tat or morphine alone, cause reversible decreases in proteasome activity. The effects of morphine on free radical production and oxidative stress are prevented by pre-treatment with naloxone, illustrating the important role of opioid receptor activation in these phenomena. While Tat is well known to induce cytokine release from cultured microglia, morphine decreases Tat-induced release of the cytokines tumor necrosis factor-alpha and interleukin-6, as well as the chemokine monocyte chemoattractant protein-1 (MCP-1). Finally, experiments using the reversible proteasome inhibitor MG115 show that temporary, non-cytotoxic decreases in proteasome activity increase protein oxidation and decrease tumor necrosis factor-alpha, interleukin-6, and MCP-1 release from microglia. Taken together, these data suggest that oxidative stress and proteasome inhibition may be involved in the immunomodulatory properties of opioid receptor activation in microglia.
Turchan-Cholewo
Jadwiga
J
Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, USA.
Dimayuga
Filomena O
FO
Gupta
Sunita
S
Keller
Jeffrey N
JN
Knapp
Pamela E
PE
Hauser
Kurt F
KF
Bruce-Keller
Annadora J
AJ
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D009020:Morphine / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D000077022:Survivin; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
D000701:Analgesics, Opioid; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C512124:HIV-TAT-survivin (T34A) protein; D007976:Leupeptins; D011480:Protease Inhibitors; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D000077022:Survivin; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; D054322:tat Gene Products, Human Immunodeficiency Virus; D009020:Morphine; D046988:Proteasome Endopeptidase Complex