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Received for publication December 10, 2003.
Revised March 23, 2004.
Accepted for publication March 29, 2004.
Interleukin-18 (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. Pre-treatments with indomethacin (2.5 mg kg-1), atenolol (1 mg kg-1) or MK886 (5-lipoxygenase activating protein inhibitor, 1 mg kg-1) did not inhibit IL-18-evoked hypernociception (40 ng paw-1), while dexamethasone (2 mg kg-1) inhibited the process. IL-18-evoked hypernociception was not inhibited by pre-treatment with antiserum to rat-TNF-
(50 µl paw-1) or IL-1 receptor antagonist (IL-1ra, 300 pg paw-1). Pre-treatment with BQ788 (ETB receptor antagonist, 3-30 nmol paw-1), but not with BQ123 (ETA receptor antagonist, 30 nmol paw-1), dose-dependently inhibited the IL-18-induced hypernociception. Pre-treatment with morphine (3-12 µg paw-1) also dose-dependently inhibited the IL-18-induced hypernociception. Moreover, endothelin-1-induced mechanical hypernociception was also inhibited by BQ788, but not by BQ123, indomethacin or atenolol. In conclusion, we demonstrated by the first time that IL-18 is a pro-hypernociceptive 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.
Key words:
Interleukin-18, cytokines, endothelin, endothelin receptor A, endothelin receptor B, inflammatory nociception
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