Activation of neuronal adenosine A1 receptors causes hypothermia through central and peripheral mechanisms

Extracellular adenosine, a danger signal, can cause hypothermia. We generated mice lacking neuronal adenosine A(1) receptors (A(1)AR, encoded by the Adora1 gene) to examine the contribution of these receptors to hypothermia. Intracerebroventricular injection of the selective A(1)AR agonist (Cl-ENBA, 5'-chloro-5'-deoxy-N-6-endo-norbornyladenosine) produced hypothermia, which was reduced in mice with deletion of A(1)AR in neurons. A non-brain penetrant A(1)AR agonist [SPA, N-6-(p-sulfophenyl) adenosine] also caused hypothermia, in wild type but not mice lacking neuronal A(1)AR, suggesting that peripheral neuronal A(1)AR can also cause hypothermia. Mice expressing Cre recombinase from the Adora1 locus were generated to investigate the role of specific cell populations in body temperature regulation. Chemogenetic activation of Adora1-Cre-expressing cells in the preoptic area did not change body temperature. In contrast, activation of Adora1-Cre-expressing dorsomedial hypothalamus cells increased core body temperature, concordant with agonism at the endogenous inhibitory A(1)AR causing hypothermia. These results suggest that A(1)AR agonism causes hypothermia via two distinct mechanisms: brain neuronal A(1)AR and A(1)AR on neurons outside the blood-brain barrier. The variety of mechanisms that adenosine can use to induce hypothermia underscores the importance of hypothermia in the mouse response to major metabolic stress or injury.