, 2003 and Yaraee et al., 2003), which is crucial to the development of the inflammatory and febrile responses and enhances the release of pro-inflammatory cytokines
in response to LPS ( Berman et al., 1996). Moreover, LPS itself can increase the NK1R expression in some of these cells ( Bost, 2004). In view of such considerations, the present study aimed to investigate, using a selective non-peptide NK1R antagonist SR140333B, whether substance P, released in the periphery or the CNS, participates in the febrile response induced by LPS and two endogenous pyrogens: IL-1β, which induces a prostaglandin-dependent fever, and CCL3/MIP-1α, which induces a prostaglandin-independent fever in conscious learn more rats. In addition, we assessed the effects of centrally administered substance P on body temperature in this species. Control animals treated only with vehicle or SR140333B showed a small increase in body temperature over baseline values, returning to pre-injection temperature after 1 h and remaining at this level up to 6 h after administration. In sharp contrast, those given LPS (30 μg/kg, i.p.) displayed an increase in body temperature that peaked after around 2.5 h and continued elevated for the remainder of the observation period. Prior injection of the NK1R antagonist SR140333B (0.3 mg/kg, data not shown or 1 mg/kg, i.p.) failed to impede the development of LPS-induced fever
(Fig. 1A and B). A higher dose of SR140333B (3 mg/kg, i.p.) was tested Z-VAD-FMK datasheet but, in combination with LPS, this dose induced a significant decrease in body temperature between 0 and 1.5 h (around 0.7 °C) after injection, which made the interpretation of the results difficult (data not shown). SR140333B (1 mg/kg, i.p.) alone did not alter body temperature from baseline (Fig. 1C). To verify if this dose of SR140333B blocked the peripheral actions of SP we examined
the effect of this treatment on protein extravasation. Intradermal injection of SP induced a significant increase in Evans blue extravasation when compared Rho to saline in vehicle-treated animals (Fig. 1D). As expected, the treatment of the animals with SR140333B, at the same dose that did not affect the febrile response, significantly reduced the protein extravasation by 81% (Fig. 1D). In the next set of experiments we injected SR140333B or the vehicle into the lateral ventricle of the animals. Control animals treated only with the vehicle or SR140333B showed much smaller changes in body temperature than in the previous set of experiments. The pre-treatment of the animals with SR140333B effectively reduced the febrile response induced by LPS (Fig. 2). Fig. 2A shows the time-course of the reduction in the febrile response induced by the higher dose of SR140333B (3 μg, i.c.v.). This dose of SR140333B reduced the fever index by 85% (Fig. 2B). A lower dose of SR140333B (1 μg, i.c.v.
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