Involvement of the NLRP3 inflammasome in the modulation of an LPS-induced inflammatory response during morphine tolerance

Background: Morphine is widely used for its analgesic effects. In addition to its high potential for addiction and tolerance, morphine also induces immunosuppression. Inflammasomes, NLRP3 being the most characterized, is a platform for activation of pro-inflammatory cytokines, particularly IL-1 beta. We have explored the effects of lipopolysaccharide (LPS) during morphine tolerance on expression of the NLRP3 inflammasome and related inflammatory genes. Methods: Morphine-pellet administration was used to induce morphine tolerance in F344 rats. Control rats were given a placebo. On day 5, the animals received either saline or 250 mu g/kg LPS. LPS-induced protein expression of TNF-alpha, IL-1 beta, and IL- 6 was examined in the spleen of rats with and without morphine tolerance. A PCR array was used to examine LPS-induced expression of 84 inflammasome-related genes with and without morphine tolerance. Results: LPS-induced IL-1 beta and TNF-alpha protein expression was significantly lower in the spleen of the morphine-tolerant animals than in the placebo-control animals. In response to LPS, expression of 27 genes, including NLRP3, TNF-alpha, IL-1 beta, and IL-6, was significantly increased, and expression of 3 genes was significantly decreased in both the morphine-tolerant and placebo-control groups compared to the saline-treated animals. However, there was only a 2.7-fold increase in NLRP3 expression in response to LPS in the morphine-tolerant rats compared to a 4.5-fold increase in the placebo-control animals. Conclusion: Our data indicate that, in the morphine-tolerant state, LPS-induced expression of NLRP3 is suppressed and cytokine/chemokine expression is inhibited, which may be one of the mechanisms involved in morphine-induced immunosuppression. (C) 2013 Published by Elsevier Ireland Ltd.