Substance P (SP) is a
neuropeptide that can modulate inflammatory mediator release through activation of
NK(1) receptors (NK(1)R). Some studies have also suggested the involvement of SP in
lipopolysaccharide (LPS)-induced
fever. However, the precise contribution of this
neuropeptide to the pathways activated during
fever is unknown. In this study we investigated the effect of a selective NK(1)R antagonist,
SR140333B, on the febrile response induced by LPS and
cytokines. Our results show that the systemic injection of
SR140333B did not modify the
fever induced by LPS at a dose that is able to reduce
protein extravasation induced by SP in the skin. On the other hand, intracerebroventricular administration of
SR140333B significantly reduced the
fever induced by peripheral injection of LPS. These data emphasize an important role for SP in the central nervous system during the febrile response to LPS, and are reinforced by the fact that intracerebroventricular injection of SP also induced
fever in a dose-dependent manner in
captopril-treated rats. Considering that the febrile response can result from the generation of several endogenous
pyrogens, among them
interleukin (IL)-1β and macrophage inflammatory protein-1α (CCL3/MIP-1α), we also examined the effect of
SR140333B on the
fever induced by these
cytokines which act through
prostaglandin-dependent and -independent mechanisms, respectively. Surprisingly,
SR140333B did not modify the febrile response to IL-1β or CCL3/MIP-1α. Altogether these data suggest that the central action of SP is essential for LPS-, but not for IL-1β- or CCL3/MIP-1α-induced
fever.