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

• Published in: The Journal of pharmacology and experimental therapeutics 2004-08, Vol.310 (2), p.710-717
• Main Authors: Verri, Jr, Waldiceu A, Schivo, Ieda R S, Cunha, Thiago M, Liew, Foo Y, Ferreira, Sergio H, Cunha, Fernando Q
• Format: Article
• Language: English
• Subjects: Animals; Endothelins - physiology; Interleukin-18 - pharmacology; Male; Morphine - pharmacology; Pain Measurement - drug effects; Pain Measurement - methods; Physical Stimulation - methods; Rats; Rats, Wistar; Receptor, Endothelin B - agonists; Receptor, Endothelin B - physiology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.063990

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[ D Trp- D Asp-Pro- D Val-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.