Abstract
Inflammatory pain can be triggered by different stimuli, such as trauma, radiation, antigen and infection. In a model of inflammatory pain caused by infection, injection in the mice paw of lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, produces mechanical hyperalgesia. We identify here the TLR4 linked signaling pathways that elicit this response. Firstly, LPS paw injection in wild type (WT) mice produced mechanical hyperalgesia that was not altered in TRIF-/- mice. On the other hand, this response was absent in TLR4 mutant and MyD88 null mice and reduced in TNFR1 null mice. Either an IL-1 receptor antagonist, anti-KC/CXCL1 antibody, indomethacin or guanethidine injection also lessened this response. Moreover, LPS-induced time dependent increases in TNF-α, KC/CXCL1 and IL-1β expression in the mice paw, which were absent in TLR4 mutant and MyD88 null mice. Furthermore, in TNFR1 deficient mice, the LPS-induced rises in KC/CXCL1 and IL-1β release were less than in their wild type counterpart. LPS also induced increase of myeloperoxidase activity in the paw skin, which was inhibited in TLR4 mutant and MyD88 null mice, and not altered in TRIF-/- mice. These results suggest that LPS-induced inflammatory pain in mice is solely dependent on the TLR4/MyD88 rather than the TLR4/TRIF signaling pathway. This pathway triggers pronociceptive cytokine TNF-α release that in turn mediates rises in KC/CXCL1 and IL-1β expression. Finally, these cytokines might be involved in stimulating production of directly-acting hyperalgesic mediators such as prostaglandins and sympathomimetic amine.
Highlights
Inflammatory pain is a common symptom of all types of inflammatory diseases
We determined whether or not LPS induces hyperalgesia in HeJ (TLR4 signalling deficient) mice (Fig. 1B). Even though this response was always induced at all times in HePas mice, it was not observed in HeJ mice. This difference indicates that Toll-like receptor 4 (TLR4)-induced cell signalling activation is required for eliciting mice paw mechanical hyperalgesia
Local treatment of mice with IL-1Ra or anti-KC/CXCL1 reduced mechanical hyperalgesia by 44% and 29%, respectively (Figure 3A). This response was reduced by indomethacin (48%), guanethidine (64%) whereas it was eliminated by coadministering both of these drugs (Figure 3B). These results suggest that TNF-a, IL-1b, KC/CXCL1, prostaglandins and sympathomimetic amines contribute to mediating LPS-induced mechanical inflammatory hyperalgesia in mice
Summary
Among the mechanisms involved in the genesis of inflammatory pain, the sensitization of pain receptor (peripheral sensitization) is a central event. This event leads to an increase in pain sensation, which is clinically referred to as hyperalgesia. Nociceptor sensitization is caused by the action of inflammatory mediators such as prostaglandins and sympathomimetic amines, which act directly on their cognate receptors expressed by primary nociceptive fibers [3,4]. In mice, carrageenin induces a concomitant release of tumor necrosis factor (TNF-a) and keratinocyte-derived chemokine (KC/CXCL1). Both mediators stimulate the subsequent release of interleukin-1b (IL-1b), which in turn induces the production of prostaglandins. It was demonstrated that during antigen-induced inflammation in immunized mice the same cytokines participate in the genesis of mechanical hyperalgesia [6]
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