Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor
Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor
复制标题
DOI：
10.1073/pnas.161292398
复制
发表时间：
2001-07-31
影响因子：
11.1
通讯作者：
Fredholm, BB
中科院分区：
文献类型：
--
作者：
Johansson, B;Halldner, L;Fredholm, BB
咖啡因被认为是通过阻断腺苷A（1）和A（2A）受体（A（1）R，A（2A）R）起作用的，这表明一些A受体是紧张性激活的。我们产生了具有A（1）R（-/-）的第二编码外显子的靶向破坏的小鼠。这些动物正常繁殖和体重增加，心率、血压和体温正常。在大多数行为测试中，它们与A（1）R（+/+）小鼠相似，但A（1）R（-/-）小鼠表现出焦虑增加的迹象。海马脑片的电生理记录显示，腺苷介导的抑制和茶碱介导的兴奋性多巴胺能神经传递的增强在A（1）R（-/-）小鼠中被消除。在A（1）R（+/-）小鼠中，腺苷的效力减半，A（1）R的数量也减半。在A（1）R（-/-）小鼠中，鞘内注射腺苷的镇痛作用丧失，并观察到热痛觉过敏，而吗啡的镇痛作用完整。缺氧后海马脑片和脑干神经元活性的下降均减少，缺氧后功能恢复减弱。因此，A（1）Rs在发育过程中并不发挥重要作用，尽管它们显着影响突触活动，但它们在正常生理学中发挥非重要作用。然而，在病理生理条件下，包括伤害性刺激和缺氧，它们是重要的。
Caffeine is believed to act by blocking adenosine A(1) and A(2A) receptors (A(1)R, A(2A)R), indicating that some A receptors are tonically activated. We generated mice with a targeted disruption of the second coding exon of the A(1)R (A(1)R(-/-)). These animals bred and gained weight normally and had a normal heart rate, blood pressure, and body temperature. In most behavioral tests they were similar to A(1)R(+/+) mice, but A(1)R(-/-) mice showed signs of increased anxiety. Electrophysiological recordings from hippocampal slices revealed that both adenosine-mediated inhibition and theophylline-mediated augmentation of excitatory glutamatergic neurotransmission were abolished in A(1)R(-/-) mice. In A(1)R(+/-) mice the potency of adenosine was halved, as was the number of A(1)R. In A(1)R(-/-) mice, the analgesic effect of intrathecal adenosine was lost, and thermal hyperalgesia was observed, but the analgesic effect of morphine was intact. The decrease in neuronal activity upon hypoxia was reduced both in hippocampal slices and in brainstem, and functional recovery after hypoxia was attenuated. Thus A(1)Rs do not play an essential role during development, and although they significantly influence synaptic activity, they play a nonessential role in normal physiology. However, under pathophysiological conditions, including noxious stimulation and oxygen deficiency, they are important.