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INFLAMMATION AND IMMUNOPHARMACOLOGY

Nociceptive Effect of Subcutaneously Injected Interleukin-12 Is Mediated by Endothelin (ET) Acting on ET_B Receptors in Rats

Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil (W.A.V., R.O.M., I.R.S.S., T.M.C., C.A.P., S.H.F., F.Q.C.); and National Institute of Biological Standards and Control, South Mimms, Hertfordshire, United Kingdom (S.P.)

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--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- (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.

Address correspondence to: Prof. Dr. Fernando de Queiroz Cunha, Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900-Ribeirão Preto, São Paulo, Brazil. E-mail address: fdqcunha{at}fmrp.usp.br

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