Impact of the Timing of Morphine Administration on Lipopolysaccharide-Mediated Lethal Endotoxic Shock in Mice.

Abstract

Sepsis is a serious condition related to systemic inflammation, organ dysfunction, and organ failure. It is a subset of the cytokine storm caused by dysregulation of cytokine production. Morphine influences the severity of infection in vivo and in vitro because it regulates cytokine production. We investigated the immunological function of morphine using a mouse model of septic shock. We treated mice with α-galactosylceramide (2 μg/mouse) to induce lethal endotoxic shock following a challenge with lipopolysaccharide (LPS, 1.5 μg/mouse). This model represents acute lung injury and respiratory failure, and reflects the clinical features of severe septic shock. We evaluated the effect of the timing of morphine (0.8 mg/mouse) administration on the survival rate, cytokine production in vivo, and histological changes of mice with LPS-mediated lethal endotoxic shock. Morphine treatment before LPS challenge suppressed lethal endotoxic shock. In contrast, when we administered after LPS, morphine exacerbated lethal endotoxic shock; hematoxylin and eosin staining revealed a marked increase in the accumulation of infiltrates comprising polymorphonuclear leukocytes and mononuclear cells in the lung; and Elastica van Gieson staining revealed the destruction of alveoli. The plasma levels of tumor necrosis factor-α, interferon-γ, monocyte-chemotactic protein-1, and interleukin-12 in the group treated with morphine after LPS challenge were higher than those treated with morphine before LPS challenge. In conclusion, one of the factors that determine whether morphine exacerbates or inhibits infection is the timing of its administration. Morphine treatment before shock improved the survival rate, and morphine treatment after shock decreased the rate of survival.