Proceedings of The Physiological Society
University of Cambridge (2004) J Physiol 555P, PC9
Systemic P2 receptor blockade attenuates increase in body temperature evoked by lipopolisaccharide in conscious rats
V.N. Gourine, D.M. Poputnikov, E.V. Melenchuk, A.V. Gourine and K.M. Spyer
Institute of Physiology, National Academy of Sciences of Belarus, Minsk 220725, Belarus and * Department of Physiology, Royal Free and University College London Medical School, London NW3 2PF, UK
Extracellular ATP acting through ionotropic P2X and metabotropic P2Y receptors, acts as a signalling molecule in the brain and periphery and has numerous physiological functions (Burnstock, 1999; North, 2002). When its role in regulation of body temperature (Tb) during infection is considered the ability to induce a release of cytokines seems to be potentially very significant. We have shown previously that ATP acting on P2 receptors in the CNS plays an important role in thermoregulation during fever (Gourine et al. 2002). In this study we investigated the effects of systemic P2 receptor blockade on regulation of Tb during fever.
Experiments were performed in adult male Wistar rats (280-350 g) and were approved by the Institutional Animal Care and Use Committee (in Minsk). Rats were anaesthetised (ketamine [87.0 mg kg-1] + xylazine [13.0 mg kg-1]) and a telemetry transmitter was implanted into the abdomen for monitoring of Tb. After a 7-day recovery period, fever was induced by intraperitoneal injection of E.coli lipopolisaccharide (LPS; 50 µg kg-1). Effects of intraperitoneal (I.P.) injection of the P2 receptor antagonists suramin (5, 25 and 100 mg kg-1), PPADS (5 and 25 mg kg-1) or saline on Tb during fever were determined. The rat was humanely killed by overdose of anaesthetic at the end of the experiment.
Following I.P. injection of LPS a fever reached a maximal Tb (around 38.5°C) 3 h after the injection. Dose-dependent attenuation of fever was observed when suramin and PPADS were injected I.P. before administration of LPS. Three h after the administration of LPS Tb of rats pretreated with suramin (100 mg kg-1) was 37.0 ± 0.4°C (mean ± S.E.M.; n = 11) some 1.6°C lower that the Tb of febrile rats injected with saline (38.6 ± 0.2°C, mean ± S.E.M.; n = 7; P = 0.018, ANOVA, post hoc Fisher's test). Similarly, 3 h after the administration of LPS Tb of rats injected with PPADS (25 mg kg-1) was 37.9 ± 0.3°C (mean ± S.E.M.; n = 7) some 0.7°C lower that the Tb of LPS-treated rats injected with saline (38.6 ± 0.1°C, mean ± S.E.M.; n = 15; P = 0.017, ANOVA, post hoc Fisher's test). Both P2 receptor antagonists had no effect on Tb in afebrile animals.
These results indicate that in the periphery ATP-mediated purinergic signalling may play very significant role in the mechanisms leading to the development of the febrile response. We propose that the attenuation of fever induced by systemic treatment with P2 receptor antagonists results from an inhibition and/or an alteration in LPS-induced cytokine release.
This work was supported by The Wellcome Trust.
Where applicable, experiments conform with Society ethical requirements