, 2007 and Oka et al., 2003) which would relief the tonic inhibition that these neurons exert over the dorsomedial hypothalamus to activate brown adipose tissue thermogenesis and over the rostral raphe pallidus to elicit cutaneous vasoconstriction (Nakamura et al., 2005, Rathner

et al., 2008 and Yoshida et al., 2009) probably through two separate pathways (Nakamura et al., 2009 and Ootsuka and McAllen, 2006). Nonetheless, how the other central mediators RG7204 interact with these neurons in the hypothalamus to produce fever is less known. There is also the possibility that different central mediators are involved in different pathways for fever induction. For example, endogenous opioids are involved in the febrile response induced by LPS and several cytokines but not by IL-1β (Fraga et al., 2008), while ET-1 is involved in the febrile response induced only by LPS and pre-formed pyrogenic factor (Fabricio et al., 2006), but not in the fever induced by other cytokines. Meanwhile, both endogenous opioids and ET-1 induce fever by prostaglandin-independent mechanisms (Fabricio et al., 2005 and Fraga et al., 2008). Although substance P may be involved in mediating certain febrile responses, its actions are not well understood. Substance P (SP: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gli-Leu-Met-NH2) is found in primary afferent fibers [A-δ, C and capsaicin-sensitive fibers (Cahill and Coderre, 2002)] as well as in the CNS

(Hurd et al., 1999), and there are several studies showing BMS354825 its participation in inflammatory processes and, to a lesser extent, in the febrile response. In the CNS, SP is present in several structures, including the POA [for review see (Otsuka and Yoshioka, 1993)]. Although the main source of SP is neuronal cells, some studies with rodents have shown that SP can also be synthesized by macrophages, eosinophils, lymphocytes, dendritic cells, and others (Bost, 2004, Ho et al., 1997 and Satake and Kawada, 2006). SP effects are mediated almost exclusively by

the metabotropic NK1R, which is expressed in several structures of the CNS, including the putamen, caudate nucleus and hypothalamus, and in the peripheral nervous system, where it is found in dorsal root ganglia and intestinal intrinsic neurons [for Methamphetamine review see (Harrison and Geppetti, 2001 and Tuluc et al., 2009)]. Furthermore, the NK1R can also be expressed by immune cells such as macrophages, neutrophils, lymphocytes and mast cells (Cooke et al., 1998, Ho et al., 1997, Lai et al., 1998 and Lambrecht et al., 1999). The administration of NK1R antagonists reduced neutrophil migration induced by P. nigriventer venom ( Costa et al., 2002) or formalin ( Santos et al., 2004), when systemically injected, and reduced the febrile response to LPS when administered centrally ( Balasko et al., 2000 and Szelenyi et al., 1997) in laboratory animals, highlighting the participation of SP in these events.