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) (ETB receptor antagonist; 3-30 nmol paw-1), but not with cyclo[DTrp-DAsp-Pro-DVal-Leu] (BQ123) (ETA 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 ETB receptor. Therefore, inhibition of the endothelin ETB receptor could be beneficial on controlling inflammatory hypernociception of diseases in which IL-18 plays a role in their pathogenesis.
Footnotes
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This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Pesquisa (Brazil), Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior, and Programa de Núcleos de Excelência, and the Chief Scientist's Office, Scotland, UK. Part of this work has been presented as an abstract at the XXXIV Brazilian Congress of Pharmacology and Experimental Therapeutics, October 28-31, 2002, Aguas de Lindoia, São Paulo, Brazil.
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DOI: 10.1124/jpet.103.063990.
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ABBREVIATIONS: IL, interleukin; IFN, interferon; Th1, T helper 1; TNF, tumor necrosis factor; CIA, collagen type II-induced arthritis; LTB4, leukotriene B4; I.pl., intraplantar; IL-1ra, interleukin-1 receptor antagonist; ET, endothelin receptor; LPS, lipopolysaccharide; ANOVA, analysis of variance.
- Received December 8, 2003.
- Accepted March 29, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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