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Brain Behav Immun. 2004 Sep;18(5):476-84.

The opioid antagonist naltrexone blocks acute endotoxic shock by inhibiting tumor necrosis factor-alpha production.

Author information

1
Department of Immunology, Institute for Biomedical Sciences, Immunology Program, The George Washington University, 2121 Eye Street N.W., Washington, DC 20052, USA.

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.

PMID:
15265541
DOI:
10.1016/j.bbi.2003.12.001
[Indexed for MEDLINE]

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