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-1β. 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 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.


RESULTS
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.


CONCLUSIONS
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.
Institute of Neuroimmune Pharmacology, Seton Hall University, 400 South Orange Avenue, South Orange, NJ 07079, USA.
Xin
X
Mao
Sraboni
S
Sarkar
Sulie L
SL
Chang
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004361:Drug Tolerance; D007249:Inflammation / Q000139:chemically induced* / Q000235:genetics*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009294:Narcotics / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002352:Carrier Proteins; D018925:Chemokines; D016207:Cytokines; D018076:DNA, Complementary; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009294:Narcotics; D014409:Tumor Necrosis Factor-alpha; D009020:Morphine
Chemokine; Cytokine; Morphine tolerance; NLRP3 inflammasome