Send to

Choose Destination
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

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


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.

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center