Abstract

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) (ET_B 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 ET_B receptor. Therefore, endothelin receptor antagonism could be beneficial in controlling IL-12 therapy-induced pain or hyperalgesia.