Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors
Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors
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DOI：
10.1124/jpet.115.229872
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发表时间：
2016-02-01
影响因子：
3.5
通讯作者：
Reitman, Marc L.
中科院分区：
文献类型：
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作者：
Carlin, Jesse Lea;Tosh, Dilip K.;Reitman, Marc L.
腺苷可以引起体温降低，就像以前对腺苷A(1)受体(A(1)AR)激动剂所证明的那样。在这里，我们使用有效的、特异的A(3)AR激动剂MRS5698、MRS5841和MRS5980来表明腺苷也通过A(3)AR诱导体温降低。A(3)AR激动剂的降温作用不依赖于A(1)AR的激活，因为这种作用在缺乏A(1)AR的小鼠中完全保持不变，而在缺乏A(3)AR的小鼠中消失。A(3)AR激动剂诱导的体温降低可被肥大细胞颗粒耗尽所减弱，表明A(3)AR体温降低至少部分是通过肥大细胞介导的。中枢剂量的激动剂没有明显的降温作用，而外周剂量的非脑穿透性激动剂引起了低温，这表明外周A(3)AR表达的细胞驱动了低温。肥大细胞释放组胺，阻断中枢组胺H-1(但不是H-2或H-4)受体可阻止体温过低。低体温之前是低代谢，低体温的小鼠更喜欢较凉爽的环境温度，这表明低体温状态是一种协调的生理反应，具有降低的体温设定点。重要的是，A(3)受体激动剂的止痛效果不需要低温，因为A(3)AR激动剂的剂量较低。这些结果支持低温的机制模型，在该模型中，A(3)AR激动剂作用于外周肥大细胞，引起组胺释放，从而刺激中枢组胺H-1受体诱导低温。这一机制表明，A(3)受体激动剂可能不适用于临床诱导体温过低。
Adenosine can induce hypothermia, as previously demonstrated for adenosine A(1) receptor (A(1)AR) agonists. Here we use the potent, specific A(3)AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A(3)AR. The hypothermic effect of A(3)AR agonists is independent of A(1)AR activation, as the effect was fully intact in mice lacking A(1)AR but abolished in mice lacking A(3)AR. A(3)AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A(3)AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non-brain-penetrant agonist caused hypothermia, suggesting that peripheral A(3)AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H-1 (but not H-2 or H-4) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A(3)AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A(3)AR agonists act on peripheralmast cells, causing histamine release, which stimulates central histamine H-1 receptors to induce hypothermia. This mechanism suggests that A(3)AR agonists will probably not be useful for clinical induction of hypothermia.