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

• Published in: The Journal of pharmacology and experimental therapeutics 2005-11, Vol.315 (2), p.609
• Main Authors: Verri, Jr, Waldiceu A, Molina, Rodrigo O, Schivo, Ieda R S, Cunha, Thiago M, Parada, Carlos A, Poole, Stephen, Ferreira, Sérgio H, Cunha, Fernando Q
• Format: Article
• Language: English
• Subjects: Analgesics; Analgesics, Opioid - pharmacology; Animals; Anti-Inflammatory Agents - pharmacology; Antibodies, Blocking - pharmacology; Cytokines - physiology; Dose-Response Relationship, Drug; Eicosanoids - pharmacology; Endothelin A Receptor Antagonists; Endothelins; Foot; Hot Temperature; Hyperalgesia - chemically induced; Hyperalgesia - psychology; Injections, Subcutaneous; Interleukin-12 - administration & dosage; Interleukin-12 - antagonists & inhibitors; Interleukin-12 - pharmacology; Male; Morphine - pharmacology; Pain - chemically induced; Pain - prevention & control; Pain Measurement - drug effects; Physical Stimulation; Rats; Rats, Wistar; Receptor, Endothelin B - drug effects; Sympathetic Nervous System - drug effects
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.089409

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[ D Trp- D Asp-Pro- D Val-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.