Proceedings of The Physiological Society
Kings College London (2005) J Physiol 565P, PC162
Role of adenosine in hypothalamic mechanisms of body temperature regulation in conscious rats
Gourine, Valery N.; Poputnikov, Dmitry ; Melenchuk, Ekaterina ; Gourine, Alexander ; Spyer, K.Michael ;
1. Physiology, Royal Free and UCL Medical School, London, United Kingdom. 2. Institute of Physiology, National Academy of Sciences of Belarus, Minsk, Belarus.
Adenosine is considered to be a major non-peptide neuromodulator in the brain and its receptors have been demonstrated to be present in the hypothalamus - in areas responsible for fine regulation of body temperature (Tb) and the development of fever. In this study we investigated the potential role of adenosine in the hypothalamic mechanisms of Tb regulation. Experiments were performed in adult male Wistar rats (280-350 g) and were approved by the Institutional Animal Care and Use Committee. Rats were anaesthetised (ketamine (87.0 mg/kg) + xylazine (13.0 mg/kg)), steel guide cannula was implanted into the anterior hypothalamus (AH), and a telemetry transmitter was implanted into the abdomen for monitoring Tb. Experiments were performed after a 7-day recovery period. Fever was induced by intraperitoneal injection of E.coli lipopolisaccharide (LPS; 50 μg/kg). Effects of intrahypothalamic administration of the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline (8-SPT, 2.5 μg, 1 μl), ecto-5′-nucleotidase inhibitor α,β-methylene ADP (α,β-meADP, 100 μg, 1 μl), A1 receptor agonist 2-chloroadenosine (5 μg, 1 μl) or artificial cerebrospinal fluid (aCSF, 1 μl) on Tb in febrile and afebrile rats were determined. The rat was humanely killed by overdose of anaesthetic at the end of the experiment. In conscious rats blockade of adenosine receptors in the AH following microinjection of 8-SPT resulted in a marked and long-lasting increase of Tb. Two hours after the injection of 8-SPT Tb of rats was 38.1±0.2°C (n=8) some 0.7°C higher than the Tb of rats injected with aCSF (37.4±0.1°C; n=7, p<0.05, Student′s t test). Four hours after treatment with 8-SPT Tb of afebrile rats was 38.6±0.3°C (n=8) some 1.2°C higher than in rats treated with aCSF (37.4±0.1°C; n=7, p<0.05, Student′s t test). Similar increases in Tb (38.7±0.3°C; n=6, p<0.05, Student's t test) were observed in rats treated into the AH with ecto-5′-nucleotidase inhibitor α,β-meADP. When the A1 receptor agonist 2-chloroadenosine was injected into the AH at the peak of LPS-induced fever a profound decrease in febrile Tb was elicited. Three hours after intrahypothalamic injection of 2-chloroadenosine Tb of febrile rats decreased to 37.6±0.1°C (n=8), 1.1°C lower than in febrile rats three hours after treatment with aCSF (38.7±0.2°C; n=6, p<0.05, Student′s t test). From these data we conclude that adenosine is released tonically at the level of the AH and that this has an action in the maintenance of Tb under euthermic conditions. We also suggest that adenosine-mediated signalling may also play a role in the hypothalamic mechanisms controlling the magnitude of the febrile response.
Where applicable, experiments conform with Society ethical requirements