A role for the neurokinin-1 receptor in endotoxin-induced fever in mice

An involvement of substance P and its receptor, the neurokinin-1 (NK1) receptor in the mediation of lipopolysaccharide (LPS)-induced fever has been shown earlier, but no studies have been performed, in which, the development of LPS-induced fever was compared between NK1 knockout (KO) and wild type (WT) mice. Adult NK1 KO and WT mice of both sexes were used. In a telemetry system, we investigated the circadian changes of deep body temperature (Tb) and locomotor activity in freely-moving NK1 KO and WT mice. In a separate set of experiments, mice were habituated to staying inside conical restrainers, then in loosely restrained NK1 KO and WT mice, their Tb and autonomic thermoeffector responses to intraperitoneal LPS (or saline) infusion were recorded. Freely-moving NK1 KO mice were hyperactive during periods of the night, which was accompanied by increased Tb, whilst there was no difference in either the locomotor activity or deep Tb between KO and WT mice during the light phase of the day. Injection of LPS resulted in a marked fever response in the mice of both genotypes (p <0.05). However, when injected with LPS, the increase of Tb in NK1 KO mice was significantly attenuated compared to controls (38.1 ± 0.2 vs. 38.5 ± 0.2°C; p <0.05). The attenuation of the fever response was caused by a reduced elevation of the heat production (oxygen consumption) in the NK1 KO mice as compared to their WT littermates (173 ± 9 vs. 189 ± 6 ml/kg/min; p <0.05). We conclude that the absence of the NK1R results in increased Tb and locomotor activity during the night with no alterations during the light phase of the day. The fever response of the NK1 KO mice is attenuated, which is, at least in part, caused by their reduced LPS-induced elevation of heat production. This work was supported by the Hungarian Scientific Research Fund (Grants PD105532 to A.G.), by the European Union (SROP-4.2.4.A/2-11-1-2012-0001 to E.Pi. and V.T.) and the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (to A.G)