title: The opioid antagonist naltrexone blocks acute endotoxic shock by inhibiting tumor necrosis factor-alpha production.
abstract: Septic shock is believed to be a consequence of excessive stimulation of the immune system by bacterial toxins that results in systemic overproduction of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), IL-1, and IL-6. Various studies have shown that TNF-alpha, a major mediator of septic shock, induces tissue injury, loss of blood pressure, organ failure, and ultimately death. Administration of the opioid antagonist naloxone has been reported to reverse opiate-mediated hypotension, promote organ perfusion and increase patient survival. In this study, we examined the mechanism by which the opioid receptor antagonist, naltrexone, modulates the septic shock response in BALB/c mice after injection with lipopolysaccharide (LPS) or staphylococcal enterotoxin B (SEB) in combination with d-galactosamine (d-gal), or with agonistic anti-Fas antibody (Jo2) alone. Each of these treatments induced rapid-onset, acute shock, and ultimately mortality (6-9h after injection), although different mechanisms are involved. Administration of the opioid antagonist naltrexone protected mice from shock induced by LPS+d-gal, but not SEB+d-gal or Jo2 antibody, a protective effect that was reversed by morphine. Naltrexone significantly inhibited the production of TNF-alpha induced by LPS, but not SEB in vivo. When bone marrow-derived, splenic or peritoneal macrophages were treated with LPS in vitro, administration of naltrexone had no direct effect on TNF-alpha production. These results suggest that naltrexone is capable of preventing LPS-induced septic shock mortality by indirect inhibition of TNF-alpha production in vivo.
authors.affiliation: Department of Immunology, Institute for Biomedical Sciences, Immunology Program, The George Washington University, 2121 Eye Street N.W., Washington, DC 20052, USA.
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Greeneltch
authors.forename: Christian C
authors.initials: CC
authors.lastname: Haudenschild
authors.forename: Achsah D
authors.initials: AD
authors.lastname: Keegan
authors.forename: Yufang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies; D001427:Bacterial Toxins; D004768:Enterotoxins; D007375:Interleukin-1 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology; D012772:Shock, Septic / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology; D019014:fas Receptor / Q000276:immunology
chemical_list: D000906:Antibodies; D001427:Bacterial Toxins; D004768:Enterotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009292:Narcotic Antagonists; D009294:Narcotics; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C031818:enterotoxin B, staphylococcal; D009271:Naltrexone; D009020:Morphine