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Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1755-60. Epub 2005 Jan 21.

A cascade of cytokines mediates mechanical inflammatory hypernociception in mice.

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  • 1Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes 3900, 14049-900, Ribeirão Preto, Brazil.


The hypernociceptive effects of cytokines [TNF-alpha, keratinocyte-derived chemokine (KC), and IL-1beta] and their participation in carrageenan (Cg)-induced inflammatory hypernociception in mice were investigated. Nociceptor sensitization (hypernociception) was quantified with an electronic version of the von Frey filament test in WT and TNF receptor type 1 knockout mice (TNF-R1-/-). TNF-alpha-induced hypernociception was abolished in TNF-R1-/- mice, partially inhibited by pretreatment with IL-1 receptor antagonist (IL-1ra) or indomethacin and unaffected by Ab against KC (AbKC) or guanethidine. IL-1ra and indomethacin pretreatment strongly inhibited the hypernociception induced by IL-1beta, which was not altered by AbKC or guanethidine or by knocking out TNF-R1. KC-induced hypernociception was abolished by AbKC, inhibited by pretreatment with indomethacin plus guanethidine, and partially inhibited by IL-1ra, indomethacin, or guanethidine. In contrast, KC-induced hypernociception was not altered by knocking out TNF-R1. Cg-induced hypernociception was abolished by administration of indomethacin plus guanethidine, diminished in TNF-R1-/- mice, and partially inhibited in WT mice pretreated with AbKC, IL-1ra, indomethacin, or guanethidine. TNF-alpha, KC, and IL-1beta concentrations were elevated in the skin of Cg-injected paws. The TNF-alpha and KC concentrations rose concomitantly and peaked before that of IL-1beta. In mice, the cytokine cascade begins with the release of TNF-alpha (acting on TNF-R1 receptor) and KC, which stimulate the release of IL-1beta. As in rats, the final mediators of this cascade were prostaglandins released by IL-1beta and sympathetic amines released by KC. These results extend to mice the concept that the release of primary mediators responsible for hypernociception is preceded by a cascade of cytokines.

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