TY - JOUR T1 - Nociceptive Effect of Subcutaneously Injected Interleukin-12 Is Mediated by Endothelin (ET) Acting on ET<sub>B</sub> Receptors in Rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 609 LP - 615 DO - 10.1124/jpet.105.089409 VL - 315 IS - 2 AU - Waldiceu A. Verri, Jr. AU - Rodrigo O. Molina AU - Ieda R. S. Schivo AU - Thiago M. Cunha AU - Carlos A. Parada AU - Stephen Poole AU - Sérgio H. Ferreira AU - Fernando Q. Cunha Y1 - 2005/11/01 UR - http://jpet.aspetjournals.org/content/315/2/609.abstract N2 - Interleukin-12 (IL-12) is an inflammatory Th1-driving cytokine that has been clinically used as immune therapy and vaccine adjuvant. Recently, it was reported that patients receiving IL-12 presented hyperalgesia. In the present study, we investigated the mechanical hyperalgesic effect of IL-12 in rats using two tests: 1) paw constant pressure and 2) electronic pressure-meter. In both tests, intraplantar administration of IL-12 (3-30 ng paw-1) caused a dose- and time-dependent mechanical hyperalgesia, which peaked between 3 to 5 h, remaining significantly different from control levels until 7 h and resolved 24 h postinjection. However, the same doses of IL-12 did not induce thermal hyperalgesia, determined using the Hargreaves test. Pretreatments with effective doses of indomethacin (2.5 mg kg-1), atenolol (1 mg kg-1), 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2,2-dimethylpropanoic acid, sodium (MK886) (5-lipoxygenase activating protein inhibitor; 1 mg kg-1), or cyclo[DTrp-DAsp-Pro-DVal-Leu] (BQ123) [endothelin (ET)A receptor antagonist; 30 nmol paw-1] did not inhibit IL-12-evoked mechanical hyperalgesia (10 ng paw-1). However, dexamethasone (2 mg kg-1), morphine (3-12 μg paw-1), and N-cys-2,6 dimethylpiperidinocarbonyl-l-γ-methylleucyl-d-1-methoxycarboyl-d-norleucine (BQ788) (ETB receptor antagonist; 3-30 nmol paw-1) did inhibit IL-12 hyperalgesia. Furthermore, neither pretreatment with effective doses of antiserum against rat-TNF-α (50 μl paw-1) nor against IL-18 (10 μg paw-1) inhibited the IL-12-induced hyperalgesia. Likewise, antiserum against IL-12 (10 ng paw-1) did not alter IL-18-induced hyperalgesia. In conclusion, we demonstrated for the first time that IL-12 is a prohyperalgesic cytokine that induces mechanical hyperalgesia mediated by endothelin action on the ETB receptor. Therefore, endothelin receptor antagonism could be beneficial in controlling IL-12 therapy-induced pain or hyperalgesia. The American Society for Pharmacology and Experimental Therapeutics ER -