Nociceptive effect of subcutaneously injected interleukin-12 is mediated by endothelin (ET) acting on ETB receptors in rats.

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[(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 microg paw(-1)), and N-cys-2,6 dimethylpiperidinocarbonyl-L-gamma-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-alpha (50 microl paw(-1)) nor against IL-18 (10 microg 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.

• Authors: Waldiceu A Verri Jr, Rodrigo O Molina, Ieda R S Schivo, Thiago M Cunha, Carlos A Parada, Stephen Poole, Sérgio H Ferreira, Fernando Q Cunha
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 315 Issue 2 Pg. 609-15 (Nov 2005) ISSN: 0022-3565 [Print] United States
• PMID: 16024732 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Analgesics, Opioid
• Anti-Inflammatory Agents
• Antibodies, Blocking
• Cytokines
• Eicosanoids
• Endothelin A Receptor Antagonists
• Endothelins
• Receptor, Endothelin B
• Interleukin-12
• Morphine

Topics

• 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, psychology)
• Injections, Subcutaneous
• Interleukin-12 (administration & dosage, antagonists & inhibitors, pharmacology)
• Male
• Morphine (pharmacology)
• Pain (chemically induced, prevention & control)
• Pain Measurement (drug effects)
• Physical Stimulation
• Rats
• Rats, Wistar
• Receptor, Endothelin B (drug effects)
• Sympathetic Nervous System (drug effects)