Mechanisms involved in IL-6-induced muscular mechanical hyperalgesia in mice.
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.
Manjavachi
Marianne Neves
MN
Department of Pharmacology, Centre of Biological Sciences, Federal University of Santa Catarina, Florianópolis 88040-900, SC, Brazil.
Motta
Emerson Marcelo
EM
Marotta
Denise Mollica
DM
Leite
Daniela Ferraz Pereira
DFP
Calixto
João B
JB
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005727:Ganglia, Spinal / Q000378:metabolism; D006596:Hexosaminidases / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced* / Q000473:pathology* / Q000517:prevention & control*; D007249:Inflammation / Q000139:chemically induced; D007273:Injections, Intramuscular / Q000379:methods; D015850:Interleukin-6 / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D010671:Phenylurea Compounds / Q000008:administration & dosage; D010766:Phosphorylation / Q000187:drug effects; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000276:immunology; D013997:Time Factors
D000906:Antibodies; D016207:Cytokines; D004791:Enzyme Inhibitors; C494200:Il6st protein, mouse; D015850:Interleukin-6; D010671:Phenylurea Compounds; D047888:Receptors, Tumor Necrosis Factor, Type I; C112019:SB 225002; C506236:Tnfrsf1a protein, mouse; D050822:Cytokine Receptor gp130; D009195:Peroxidase; D020929:Mitogen-Activated Protein Kinase Kinases; D006596:Hexosaminidases