title: Antigen-induced inflammatory mechanical hypernociception in mice is mediated by IL-18.
abstract: There is pre-clinical evidence that therapies targeting IL-18 might be beneficial in controlling arthropathies, which are accompanied by hypernociception (nociceptor sensitization). In the present study, we addressed the hypernociceptive role of IL-18 in a model of antigen-induced inflammation in mice and its mechanisms. In naïve mice, the intraplantar injection of IL-18 induced dose- and time-dependent mechanical hypernociception, which was inhibited in IFN-gamma deficient (-/-) mice, and by the pre-treatment with bosentan (dual endothelin [ET] receptor antagonist), BQ123 (ET(A) receptor antagonist) or indomethacin (cyclooxygenase inhibitor). IL-18 hypernociception was unaffected in TNFR1(-/-) mice or by the pre-treatment with sIL-15Ralpha (soluble form of IL-15 receptor), BQ788 (ET(B) receptor antagonist) or guanethidine (sympathetic blocker). The ovalbumin (OVA) challenge-induced mechanical hypernociception in immunized mice was inhibited by the pre-treatment with anti-IL-18 antibody or in IL-18(-/-) mice. Furthermore, IL-18 induced significant IFN-gamma production in the paw skin of naïve mice. The OVA challenge-induced IFN-gamma and ET-1 productions were inhibited in IL-18(-/-) immunized mice, as well as ET-1 production in IFN-gamma(-/-) immunized mice. In addition, significant PGE2 production was detected after IL-18 or ET-1 (via ET(A) receptors) injection in naïve mice. Taken together with previous data, these results suggest that IL-18 plays a significant role in antigen-induced inflammatory hypernociception via the production of IFN-gamma, ET-1 and PGE2. Thus, IL-18 and IL-18-downstream mediators demonstrated herein might constitute targets to inhibit antigen-induced inflammatory pain.
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, São Paulo, Brazil.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Parada
authors.forename: Stephen
authors.initials: S
authors.lastname: Poole
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: Sérgio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D020382:Interleukin-18 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D010146:Pain / Q000276:immunology*; D017288:Pain Threshold / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000276:immunology / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013314:Stress, Mechanical; D013997:Time Factors
chemical_list: D000941:Antigens; D020382:Interleukin-18; D044022:Receptor, Endothelin A; D047888:Receptors, Tumor Necrosis Factor, Type I; D007371:Interferon-gamma; D010047:Ovalbumin; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone