Interleukin-18 Induces Mechanical Hypernociception in Rats via Endothelin Acting on ETBReceptors in a Morphine-Sensitive Manner

Abstract

Interleukin (IL)-18 has an important role in the pathogenesis of arthritis, which is accompanied by movement limitation secondary to inflammatory articular nociception. Therefore, we investigated the possible mechanical hypernociceptive effect of IL-18 in rats using the paw constant pressure and the electronic pressure-meter tests. In both tests, intraplantar administration of IL-18 (20-60 ng paw^-1) caused a dose- and time-dependent mechanical hypernociception, which peaked 3 h and reached control levels 24 h after injection. Pretreatments with indomethacin (2.5 mg kg^-1), atenolol (1 mg kg^-1), or 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2;2-dimethylpropanoic acid; Na (MK886) (5-lipoxygenase-activating protein inhibitor; 1 mg kg^-1) did not inhibit IL-18-evoked hypernociception (40 ng paw^-1), whereas dexamethasone (2 mg kg^-1) inhibited the process. IL-18-evoked hypernociception was not inhibited by pretreatment with antiserum to rat tumor necrosis factor-α (50 μl paw^-1) or IL-1 receptor antagonist (300 pg paw^-1). Pretreatment with N-cys-2,6 dimethylpiperidinocarbonyl-l-γ-methylleucyl-d-1-methoxycarboyl-d-norleucine (BQ788) (ET_B receptor antagonist; 3-30 nmol paw^-1), but not with cyclo[_DTrp-_DAsp-Pro-_DVal-Leu] (BQ123) (ET_A receptor antagonist; 30 nmol paw^-1), dose dependently inhibited the IL-18-induced hypernociception. Pretreatment with morphine (3-12 μg paw^-1) also dose-dependently inhibited the IL-18-induced hypernociception. Moreover, endothelin-1-induced mechanical hypernociception also was inhibited by BQ788, but not by BQ123, indomethacin, or atenolol. In conclusion, we demonstrated for the first time that IL-18 is a prohypernociceptive cytokine that induces mechanical hypernociception mediated by endothelin, via ET_B receptor. Therefore, inhibition of the endothelin ET_B receptor could be beneficial on controlling inflammatory hypernociception of diseases in which IL-18 plays a role in their pathogenesis.