Role of IL-18 in overt pain-like behaviour in mice

Abstract

There are evidences that targeting IL-18 might be beneficial to inhibit inflammatory symptoms, including hypernociception (decrease in nociceptive threshold). The mechanism of IL-18 mechanical hypernociception depends on endothelin in rats and mice. However, the role of IL-18 in overt pain-like behaviour remains undetermined. Therefore, we addressed the role of IL-18 in writhing response induced by intraperitoneal (i.p.) injection of phenyl- p-benzoquinone (PBQ) and acetic acid in mice. Firstly, it was detected that PBQ and acetic acid i.p. injection induced a dose-dependent number of writhes in Balb/c mice. Subsequently, it was observed that the PBQ — but not the acetic acid-induced writhes were diminished in IL-18 deficient ( −/−) mice. Therefore, considering that IFN-γ, endothelin and prostanoids mediate IL-18-induced mechanical hypernociception, we also investigated the role of these mediators in the same model of writhing response in which IL-18 participates. It was noticed that PBQ-induced writhes were diminished in IFN-γ −/− mice and by the treatment with bosentan (mixed endothelin ET A/ET B receptor antagonist), BQ 123 (cyclo[DTrp-DAsp-Pro-DVal-Leu], selective endothelin ET A receptor antagonist), BQ 788 ( N- cys-2,6 dimethylpiperidinocarbonyl- l-methylleucyl- d-1-methoxycarboyl- d-norleucine, selective endothelin ET B receptor antagonist) or indomethacin (cycloxigenase inhibitor). Thus, IL-18, IFN-γ, endothelin acting on endothelin ET A and ET B receptors, and prostanoids mediate PBQ-induced writhing response in mice. To conclude, these results further advance the understanding of the physiopathology of overt pain-like behaviour, and suggest for the first time a role for IL-18 in writhing response in mice.