Institute of Neuroimmune Pharmacology, Seton Hall University, 400 South Orange Avenue, South Orange, NJ 07079, USA.
Drug Alcohol Depend. 2013 Sep 1;132(1-2):38-46. doi: 10.1016/j.drugalcdep.2012.12.022. Epub 2013 Jan 23.
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-1β. We have explored the effects of lipopolysaccharide (LPS) during morphine tolerance on expression of the NLRP3 inflammasome and related inflammatory genes.
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 μg/kg LPS. LPS-induced protein expression of TNF-α, IL-1β, 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.
LPS-induced IL-1β and TNF-α 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-α, IL-1β, 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.
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.
吗啡因其镇痛作用而被广泛应用。除了具有高度成瘾性和耐受性外，吗啡还会引起免疫抑制。炎性小体，其中 NLRP3 是最具特征的一种，是激活前炎性细胞因子（特别是 IL-1β）的平台。我们探索了吗啡耐受期间脂多糖（LPS）对 NLRP3 炎性小体和相关炎症基因表达的影响。
使用吗啡丸给药来诱导 F344 大鼠的吗啡耐受。对照组大鼠给予安慰剂。第 5 天，动物接受生理盐水或 250μg/kg LPS。检查吗啡耐受和无吗啡耐受大鼠脾脏中 LPS 诱导的 TNF-α、IL-1β 和 IL-6 蛋白表达。使用 PCR 阵列检查吗啡耐受和无吗啡耐受大鼠 LPS 诱导的 84 种炎性小体相关基因的表达。
与安慰剂对照组动物相比，吗啡耐受动物脾脏中 LPS 诱导的 IL-1β 和 TNF-α 蛋白表达明显降低。对 LPS 的反应中，27 种基因，包括 NLRP3、TNF-α、IL-1β 和 IL-6 的表达显著增加，与生理盐水处理的动物相比，吗啡耐受和安慰剂对照组动物中 3 种基因的表达显著降低。然而，与安慰剂对照组动物相比，吗啡耐受大鼠对 LPS 的 NLRP3 表达仅增加了 2.7 倍，而安慰剂对照组动物增加了 4.5 倍。
我们的数据表明，在吗啡耐受状态下，LPS 诱导的 NLRP3 表达受到抑制，细胞因子/趋化因子表达受到抑制，这可能是吗啡引起免疫抑制的机制之一。
