title: Lipopolysaccharide induces inflammatory hyperalgesia triggering a TLR4/MyD88-dependent cytokine cascade in the mice paw.
abstract: Inflammatory pain can be triggered by different stimuli, such as trauma, radiation, antigen and infection. In a model of inflammatory pain caused by infection, injection in the mice paw of lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, produces mechanical hyperalgesia. We identify here the TLR4 linked signaling pathways that elicit this response. Firstly, LPS paw injection in wild type (WT) mice produced mechanical hyperalgesia that was not altered in TRIF-/- mice. On the other hand, this response was absent in TLR4 mutant and MyD88 null mice and reduced in TNFR1 null mice. Either an IL-1 receptor antagonist, anti-KC/CXCL1 antibody, indomethacin or guanethidine injection also lessened this response. Moreover, LPS-induced time dependent increases in TNF-α, KC/CXCL1 and IL-1β expression in the mice paw, which were absent in TLR4 mutant and MyD88 null mice. Furthermore, in TNFR1 deficient mice, the LPS-induced rises in KC/CXCL1 and IL-1β release were less than in their wild type counterpart. LPS also induced increase of myeloperoxidase activity in the paw skin, which was inhibited in TLR4 mutant and MyD88 null mice, and not altered in TRIF-/- mice. These results suggest that LPS-induced inflammatory pain in mice is solely dependent on the TLR4/MyD88 rather than the TLR4/TRIF signaling pathway. This pathway triggers pronociceptive cytokine TNF-α release that in turn mediates rises in KC/CXCL1 and IL-1β expression. Finally, these cytokines might be involved in stimulating production of directly-acting hyperalgesic mediators such as prostaglandins and sympathomimetic amine.
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Igor L
authors.initials: IL
authors.lastname: Calil
authors.affiliation: Departamento de Patologia, Centro de Ciências Biologicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zarpelon
authors.affiliation: FIOCRUZ Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.
authors.forename: Ana T G
authors.initials: AT
authors.lastname: Guerrero
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Alves-Filho
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Departamento de Patologia, Centro de Ciências Biologicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D005528:Foot / Q000473:pathology; D006930:Hyperalgesia / Q000139:chemically induced*; D007249:Inflammation / Q000139:chemically induced*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013314:Stress, Mechanical; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4