Activation of adenosine A_2A or A_2B receptors causes hypothermia in mice

Extracellular adenosine is a danger/injury signal that initiates protective physiology, such as hypothermia. Adenosine has been shown to trigger hypothermia via agonism at A₁ and A₃ adenosine receptors (A₁AR, A₃AR). Here, we find that adenosine continues to elicit hypothermia in mice null for A₁AR and A₃AR and investigated the effect of agonism at A_2AAR or A_2BAR. The poorly brain penetrant A_2AAR agonists CGS-21680 and PSB-0777 caused hypothermia, which was not seen in mice lacking A_2AAR. MRS7352, a likely non-brain penetrant A_2AAR antagonist, inhibited PSB-0777 hypothermia. While vasodilation is probably a contributory mechanism, A_2AAR agonism also caused hypometabolism, indicating that vasodilation is not the sole mechanism. The A_2BAR agonist BAY60-6583 elicited hypothermia, which was lost in mice null for A_2BAR. Low intracerebroventricular doses of BAY60-6583 also caused hypothermia, indicating a brain site of action, with neuronal activation in the preoptic area and paraventricular nucleus of the hypothalamus. Thus, agonism at any one of the canonical adenosine receptors, A₁AR, A_2AAR, A_2BAR, or A₃AR, can cause hypothermia. This four-fold redundancy in adenosine-mediated initiation of hypothermia may reflect the centrality of hypothermia as a protective response.