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.