The hypernociceptive effects of cytokines [TNF-␣, keratinocytederived chemokine (KC), and IL-1␤] 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-␣-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-1␤, 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-␣, KC, and IL-1␤ concentrations were elevated in the skin of Cg-injected paws. The TNF-␣ and KC concentrations rose concomitantly and peaked before that of IL-1␤. In mice, the cytokine cascade begins with the release of TNF-␣ (acting on TNF-R1 receptor) and KC, which stimulate the release of IL-1␤. As in rats, the final mediators of this cascade were prostaglandins released by IL-1␤ 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.inflammation ͉ prostaglandins ͉ TNF ͉ hyperalgesia ͉ pain C ytokines are produced by various cells types in response to a variety of stimuli and constitute a link between cellular injury or recognition of nonself and the development of local and systemic signs and symptoms of inflammation (1-5). Acute inflammatory pain is characterized by hypernociception due to the sensitization of primary sensory nociceptive neurons, also referred to as hyperalgesia or allodynia (6). After tissue injury, specific primary mediators are released that act on membrane neuronal metabotropic receptors to trigger the activation of second messenger pathways. Eicosanoids and sympathetic amines are the most important primary mediators ultimately responsible for mechanical hypernociception in rats (7-9). These mediators activate second messenger pathways (cAMP, protein kinase A, and PKC) responsible for lowering the nociceptor threshold and increasing neuronal membrane excitability. In this state, nociceptor activation and impulse transmission by the primary nociceptive neurons are facilitated (7,(10)(11)(12)(13)(14)(15)(16)(17).In the last decade, it has been shown that inflammatory stimuli do not directly stimulate the release of primary hypernocic...

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IL-33/ST2 signalling triggers the production of inflammatory mediators contributing to carrageenin-induced inflammation. These data reinforces the importance of IL-33/ST2 signalling as a target in innate inflammation and inflammatory pain.

We have studied the mechanism by which interleukin-8 (IL-8) induces fever in rats. Intracerebroventricular injections of IL-8 (5.5-50 ng) evoked dose-dependent increases in body temperature, which reached a plateau 5 h after injection, i.e., later than intracerebroventricular interleukin-1 beta (IL-1 beta; 2 h). The pyrogenic activity of IL-8 was not due to contamination with lipopolysaccharide (LPS) because preincubation of IL-8 with a specific antibody or boiling the IL-8 for 30 min abolished its activity but not that of LPS; also, IL-8 but not LPS induced fever in LPS-tolerant rats. Indomethacin significantly reduced the pyrogenic effects of intracerebroventricular injections of LPS and IL-1 beta but not responses to IL-8, suggesting that pyrogenic responses to IL-8 were mediated independently of prostaglandins. In contrast, dexamethasone markedly attenuated pyrogenic responses to IL-8 and IL-1 beta. These data suggest that inhibition of IL-8 by glucocorticoids contributes to the antipyretic effects of these drugs in fevers resistant to cyclooxygenase inhibitors.