Nociceptive effect of subcutaneously injected interleukin-12 is mediated by endothelin (ET) acting on ETB receptors in rats.
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.
Verri
Waldiceu A
WA
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
Molina
Rodrigo O
RO
Schivo
Ieda R S
IR
Cunha
Thiago M
TM
Parada
Carlos A
CA
Poole
Stephen
S
Ferreira
Sérgio H
SH
Cunha
Fernando Q
FQ
D000700:Analgesics; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D019138:Antibodies, Blocking / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000494:pharmacology; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins; D005528:Foot; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000523:psychology; D007279:Injections, Subcutaneous; D018664:Interleukin-12 / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced* / Q000517:prevention & control*; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D044023:Receptor, Endothelin B / Q000187:drug effects*; D013564:Sympathetic Nervous System / Q000187:drug effects
D000700:Analgesics; D000701:Analgesics, Opioid; D000893:Anti-Inflammatory Agents; D019138:Antibodies, Blocking; D016207:Cytokines; D015777:Eicosanoids; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins; D044023:Receptor, Endothelin B; D018664:Interleukin-12; D009020:Morphine