Interleukin-6 (IL-6) is an inflammatory
cytokine known to modulate
muscle pain. However, the mechanisms underlying this effect still remain unclear. Here we show that the injection of
IL-6 into mice gastrocnemius muscle evoked a time- and dose-dependent
mechanical hyperalgesia. This effect is in part dependent on the presence of gp130 expression in inflammatory cells in the gastrocnemius muscle as well as in DRG neurons. We also demonstrated an increased inflammatory cell recruitment and
cytokines levels, namely TNF-α, IL-1β and KC.
TNFR1(-/-) mice or mice pre-treated with the selective CXCR2 antagonist,
SB225002, with the anti-macrophage, anti-TNF-α or anti-KC
antibodies or with
IL-1 receptor antagonist (IL-1RA) showed decreased IL-6-mediated
mechanical hyperalgesia. Furthermore, systemic pre-treatment with the classically used drugs
indomethacin,
celecoxib, guanetidine,
morphine,
thalidomide or
dexamethasone, also prevented IL-6-induced
muscle pain. Likewise, local pre-treatment with inhibitors of
phospholipase A2 (
PACOCF3),
phospholipase C (
U73122),
protein kinase C (
GF109203X),
protein kinase A (KT-5720) or with
phosphatidylinositol 3-kinase (AS605204) also consistently diminished IL-6-induced muscle
hyperalgesia. The
intramuscular injection of the selective inhibitors of
p38 MAPK (
SB203580), ERK (
PD98059) or JNK (SP60015) also prevented IL-6-mediated muscular
pain. Simultaneous flow cytometry measurements revealed that ERK,
p38 MAPK and JNK were phosphorylated as early as 5 min after
IL-6 injection. These findings provided new evidence indicating that
IL-6 exerts a relevant role in the development and maintenance of muscular
hyperalgesia. The IL-6-mediated muscular
pain response involves resident cell activation, polymorphonuclear cell infiltration,
cytokine production,
prostanoids and
sympathomimetic amines release and the activation of intracellular pathways, especially MAPKs.