Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
Neuropharmacology. 2018 Sep 1;139:268-278. doi: 10.1016/j.neuropharm.2018.02.035. Epub 2018 Mar 13.
Extracellular adenosine is a danger/injury signal that initiates protective physiology, such as hypothermia. Adenosine has been shown to trigger hypothermia via agonism at A and A adenosine receptors (AAR, AAR). Here, we find that adenosine continues to elicit hypothermia in mice null for AAR and AAR and investigated the effect of agonism at AAR or AAR. The poorly brain penetrant AAR agonists CGS-21680 and PSB-0777 caused hypothermia, which was not seen in mice lacking AAR. MRS7352, a likely non-brain penetrant AAR antagonist, inhibited PSB-0777 hypothermia. While vasodilation is probably a contributory mechanism, AAR agonism also caused hypometabolism, indicating that vasodilation is not the sole mechanism. The AAR agonist BAY60-6583 elicited hypothermia, which was lost in mice null for AAR. 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, AAR, AAR, AAR, or AAR, can cause hypothermia. This four-fold redundancy in adenosine-mediated initiation of hypothermia may reflect the centrality of hypothermia as a protective response.
细胞外腺苷是一种危险/损伤信号，它会引发保护性生理反应，如体温降低。研究表明，腺苷通过与 A 和 A 腺苷受体（AAR、AAR）的激动作用引发体温降低。在这里，我们发现，在缺乏 AAR 和 AAR 的小鼠中，腺苷仍能引发体温降低，并研究了 AAR 或 AAR 激动作用的影响。脑穿透性差的 AAR 激动剂 CGS-21680 和 PSB-0777 引起体温降低，但在缺乏 AAR 的小鼠中未观察到这种情况。MRS7352 是一种可能非脑穿透性的 AAR 拮抗剂，可抑制 PSB-0777 引起的体温降低。虽然血管舒张可能是一个促成机制，但 AAR 激动作用也导致代谢降低，表明血管舒张不是唯一的机制。AAR 激动剂 BAY60-6583 引起体温降低，但在缺乏 AAR 的小鼠中失去作用。低脑室内剂量的 BAY60-6583 也引起体温降低，表明存在作用部位，在下丘脑视前区和室旁核神经元激活。因此，任何一种经典的腺苷受体，AAR、AAR、AAR 或 AAR，的激动作用都能引起体温降低。腺苷介导的体温降低的这种四重冗余可能反映了体温降低作为一种保护反应的核心地位。
