Febrigenic signaling to the brain does not involve nitric oxide

Abstract

1 The involvement of peripheral nitric oxide (NO) in febrigenic signaling to the brain has been proposed because peripherally administered NO synthase (NOS) inhibitors attenuate lipopolysaccharide (LPS)-induced fever in rodents. However, how the unstable molecule of NO can reach the brain to trigger fever is unclear. It is also unclear whether NOS inhibitors attenuate fever by blocking febrigenic signaling or, alternatively, by suppressing thermogenesis in brown fat. 2 Male Wistar rats were chronically implanted with jugular catheters; their colonic and tail skin temperatures (T c and T sk ) were monitored. 3 Study 1 was designed to determine whether the relatively stable, physiologically relevant forms of NO, that is, S-nitrosoalbumin (SNA) and S-nitrosoglutathione (SNG), are pyrogenic and whether they enhance LPS fever. At a neutral ambient temperature (T a ) of 311C, afebrile or LPS (1 mg kg À1 , i.v.)-treated rats were infused i.v. with SNA (0.34 or 4.1 mmol kg À1; the controls received NaNO 2 and albumin) or SNG (10 or 60 mmol kg À1 ; the controls received glutathione). T c of SNA-or SNG-treated rats never exceeded that of the controls. 4In Study 2, we tested whether the known fever-attenuating effect of the NOS inhibitor N o -nitro-Larginine methyl ester (L-NAME) at a subneutral T a (when fever is brought about by thermogenesis) also occurs at a neutral T a (when fever is brought about by skin vasoconstriction). At a subneutral T a of 241C, L-NAME (2.5 mg kg À1, i.v.) attenuated LPS (10 mg kg À1, i.v.) fever, presumably by inhibiting thermogenesis. At 311C, L-NAME enhanced LPS fever by augmenting skin vasoconstriction (T sk fall). 5 In summary, both SNA and SNG had no pyrogenic effect of their own and failed to enhance LPS fever; peripheral L-NAME attenuated only fever brought about by increased thermogenesis. It is concluded that NO is uninvolved in febrigenic signaling to the brain.

Lipopolysaccharide fever is initiatedviaa capsaicin-sensitive mechanism independent of the subtype-1 vanilloid receptor

“…In the rat, moderate intravenous doses of bacterial lipopolysaccharide (LPS) induce a polyphasic fever consisting of at least three consecutive body temperature rises -three phases (Romanovsky et al, 1998a, b). Although its magnitude is small (often just a few tenths of a degree), the first febrile phase is highly reproducible (Sze´kely & Szele´nyi, 1979;Romanovsky et al, 1996;1998a, b;Sze´kely et al, 2000;2003a;Dogan et al, 2003;Steiner et al, 2004) and reliably detectable by a separate burst of thermoeffector activity (i.e. a decrease in tail skin blood flow) or as a separate loop in a phase-plane plot (either the first time derivative of body temperature or thermoeffector activity plotted against body temperature; see Romanovsky et al, 1998a, b).…”

Leptin: At the crossroads of energy balance and systemic inflammation

“…104-107. Three febrile phases have been identified in the rat [107][108][109][110][111] and mouse [106,112,113]. Interestingly, when an LPS dose that normally causes polyphasic fever at a neutral ambient temperature is given to a rat in a cool environment, it causes hypothermia (which may or may not be followed by fever); see Fig.…”

Regulation of MyD88-Dependent Signaling Events by S Nitrosylation Retards Toll-Like Receptor Signal Transduction and Initiation of Acute-Phase Immune Responses

“…After 30 min of administration, lung was excised and then lysed for immunoblot analysis. The febrile responses in mice treated with E. coli LPS were tested according to a protocol described previously (45,49). Mice (n ϭ 6) were maintained at a neutral ambient temperature of 31°C and challenged by intraperitoneal (i.p.)…”