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October 16, 2012
1:00:00 PM - 4:00:00 PM
Room Hall C-Area L
Opioids Inhibit Lipopolysaccharide-Mediated Lethal Shock in Mice
Tomoko Fukada, M.D., RIka Nakayama, M.D., Hiroko Iwakiri, M.D., Hidehito Kato, M.D., Junji Yagi, M.D., Makoto Ozaki, M.D.
Tokyo Women's Medical University, School of Medicine, Tokyo, Japan

Sepsis is a serious condition characterized by systemic inflammation, organ dysfunction and failure, and associated cytokine storm.

Morphine and other opioids, which are used for treating pain in the perioperative period, are potent immunomodulators. Opioids increased survival rate in our lipopolysaccharide (LPS)-mediated lethal shock mice model. Therefore, we examined whether the increased survival was mediated by the μ-opioid receptor in vivo and in vitro.

Materials and Methods

1. Induction of LPS-mediated lethal shock

All animal procedures and protocols were approved by the Ethics Committee on Animal Experimentation of Tokyo Women’s Medical University.

Mice (female C57BL/6 mice; age, 6-8 weeks; weight, 20-25 g) were injected intraperitoneally with LPS after a subcutaneous injection of αgalactosylceramide (α-GalCer). This model is consistent with the clinical features of severe septic shock.

2. Survival of LPS-mediated lethal shock mice

Mice received morphine, naloxone, butorphanol, or phosphate buffered saline subcutaneously before an intraperitoneal injection of α-GalCer and LPS or between an intraperitoneal injection of α-GalCer and LPS. Survival rate was recorded every 12 hours.

3. Effect of morphine on cytokine production in vivo and histological changes in the LPS-mediated lethal shock mice model

Mice received morphine subcutaneously after an intraperitoneal injection of α-GalCer and before an intraperitoneal injection of LPS. Cytokines were measured over time and various organs were removed, and stained using hematoxylin and eosin (HE).

4. Inhibitory effect of morphine and naloxone on cytokine production in vitro

Spleen cells, and peritoneal exudate cells (PEC) collected from mice administered α-GalCer were incubated with pigeon cytochrome C or with the specific μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTOP). Subsequently, spleen cells and PEC were incubated with morphine or naloxone and then cultured with LPS. The supernatant was collected and assayed for concentrations of cytokines by beads array.

Results and Discussion

1. Morphine and naloxone improved the survival; both opioids bound to the μ-opioid receptor, although morphine acted as an agonist and naloxone acted as an antagonist. In contrast, butorphanol, which binds to the κ-opioid receptor, did not reduce the lethality. Therefore, binding to the μ-opioid receptor strongly influenced survival of LPS-mediated lethal shock in the mice.

2. In vivo: Morphine inhibited the production of tumor necrosis factor-α, interferon (IFN)-γ, monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-12, and IL-6 as well as the accumulation of a large number of infiltrates consisting of polymorphonuclear leukocytes and mononuclear cells in the lungs. Therefore, inhibiting production of these cytokines using morphine improved the survival.

3. In vitro: Morphine and naloxone inhibited production of IFN-γ and MCP-1 in spleen cell and PEC, respectively, which were collected from mice stimulated using LPS. CTOP, which binds to the μ-opioid receptor specifically, blocked the effects of morphine and naloxone. Therefore, it was important that opioids, such as morphine and naloxone, bound to the μ-opioid receptor to improve survival of LPS-mediated lethal shock in mice.


Binding of morphine and naloxone to the μ-opioid receptor improved survival of LPS-mediated lethal shock in the mice model, which is consistent with the clinical features of severe septic shock. Therefore, morphine and naloxone may inhibit the cytokine storm and increase the survival rate of patients in clinical shock, considering administration time, route, and dose of opioid.

Copyright © 2012 American Society of Anesthesiologists