Interleukin-18 Induces Mechanical Hypernociception in Rats via Endothelin Acting on ET B Receptors in a Morphine- Sensitive Manner Waldiceu A. Verri Jr., Ieda R. S. Schivo, Thiago M. Cunha, Foo Y. Liew, Sergio H. Ferreira, and Fernando Q. Cunha Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sa ˜ o Paulo, Sa ˜ o Paulo, Brazil (W.A.V.J., I.R.S.S., T.M.C., S.H.F., F.Q.C.); and Division of Immunology, Infection, and Inflammation, University of Glasgow, Glasgow, United Kingdom (F.Y.L.) Received December 8, 2003; accepted March 29, 2004 ABSTRACT Interleukin (IL)-18 has an important role in the pathogenesis of arthritis, which is accompanied by movement limitation sec- ondary 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 indometh- acin (2.5 mg kg -1 ), atenolol (1 mg kg -1 ), or 3-[1-(p-chloroben- zyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2;2-dimethylpro- panoic acid; Na (MK886) (5-lipoxygenase-activating protein inhibitor; 1 mg kg -1 ) did not inhibit IL-18-evoked hypernoci- ception (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- (50 l paw -1 ) or IL-1 receptor antagonist (300 pg paw -1 ). Pretreatment with N-cys-2,6 dimethylpiperidinocar- bonyl- L- -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 an- tagonist; 30 nmol paw -1 ), dose dependently inhibited the IL- 18-induced hypernociception. Pretreatment with morphine (3–12 g 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 prohypernocicep- tive cytokine that induces mechanical hypernociception medi- ated by endothelin, via ET B receptor. Therefore, inhibition of the endothelin ET B receptor could be beneficial on controlling in- flammatory hypernociception of diseases in which IL-18 plays a role in their pathogenesis. Interleukin (IL)-18, identified as an interferon (IFN)-- inducing factor, is a member of the IL-1 family due to its structural homology and because it shares IL-1-converting enzyme (caspase 1) to cleave its precursor pro-IL-18, yielding an active 18-kDa glycoprotein (for review, see Nakanishi et al., 2001). IL-18 mRNA is expressed by various cell types, including macrophages, dendritic, osteoblasts, and intestinal epithelial cells (McInnes et al., 2000). IL-18 has a variety of biological functions, including the stimulation of the prolif- eration of activated T cells, enhancement of natural killer cells lytic activity, and IFN- production by T helper 1 (Th1), CD8 + , and natural killer cells in mice and in humans (Hoshino et al., 1999; for review, Nakanishi et al., 2001). Although IL-18 itself cannot induce strong IFN- expression, IL-18 fully induces IFN- production in synergy with IL-12. IL-18 itself cannot induce Th1 differentiation, but it potenti- ates IL-12-driven Th1 development (Hoshino et al., 1999). Recent reports indicate a role for IL-18 in the pathogenesis of several inflammatory diseases. In humans, IL-18 expres- sion has been reported in sepsis, hepatitis C virus infection, Crohn’s disease, and type I diabetes (McInnes et al., 2000; for This work was supported by grants from Fundac ¸a ˜o de Amparo a ` Pesquisa do Estado de Sa ˜ o Paulo, Conselho Nacional de Pesquisa (Brazil), Coordena- doria de Aperfeic ¸oamento de Pessoal de Nı ´vel Superior, and Programa de Nu ´ cleos de Excele ˆncia, 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, Sa ˜ o Paulo, Brazil. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.103.063990. ABBREVIATIONS: IL, interleukin; IFN, interferon; Th1, T helper 1; TNF, tumor necrosis factor; CIA, collagen type II-induced arthritis; LTB 4 , leukotriene B 4 ; I.pl., intraplantar; IL-1ra, interleukin-1 receptor antagonist; ET, endothelin receptor; LPS, lipopolysaccharide; ANOVA, analysis of variance. 0022-3565/04/3102-710 –717$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 310, No. 2 Copyright © 2004 by The American Society for Pharmacology and Experimental Therapeutics 63990/1157387 JPET 310:710–717, 2004 Printed in U.S.A. 710 at ASPET Journals on May 31, 2016 jpet.aspetjournals.org Downloaded from