Activation of the Orexin 1 Receptor is a Critical Component of CO2-Mediated Anxiety and Hypertension but not Bradycardia
Activation of the Orexin 1 Receptor is a Critical Component of CO2-Mediated Anxiety and Hypertension but not Bradycardia
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DOI：
10.1038/npp.2012.38
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发表时间：
2012-07-01
影响因子：
7.6
通讯作者：
Shekhar, Anantha
中科院分区：
文献类型：
--
作者：
Johnson, Philip L.;Samuels, Brian C.;Shekhar, Anantha
急性高碳酸血症（动脉CO2/H+升高）是一种窒息信号，可危及生命，并迅速调动呼吸和行为觉醒的适应性变化，以恢复酸碱平衡。呼吸系统疾病（如哮喘或支气管炎、慢性阻塞性肺病（COPD））中出现的重度高碳酸血症也会导致高度焦虑和自主神经激活。最近的证据表明，唤醒促进下丘脑brexin（ORX：也称为hypocretin）神经元对CO2/H+的局部变化高度敏感，缺乏prepro-ORX的小鼠对高碳酸血症的呼吸反应迟钝。此外，在最近的临床研究中，容易穿过血脑屏障的ORX-A在患有COPD和高碳酸呼吸衰竭的患者的血浆中显著增加。这与CORD的啮齿动物模型一致，其中慢性暴露于香烟烟雾导致下丘脑ORX-A表达增加三倍。在本研究中，我们确定了ORX在焦虑样行为和心肺反应中的作用，以急性暴露于阈值恐慌挑战（即，20%CO2/常氧气体）。将清醒的大鼠暴露于这种高碳酸血症，而不是大气中，导致呼吸，升压和心动过缓反应，以及焦虑样行为和增加ORX神经元中的细胞c-Fos反应。全身性地，用中枢活性ORX 1受体拮抗剂（30 mg/kg SB 334867）预处理大鼠可减弱高碳酸气体诱导的升压和焦虑反应，而不会改变稳健的心动过缓反应，并且仅在CO2激发抵消时减弱呼吸反应。我们的研究结果表明，ORX系统在高碳酸血症的焦虑和交感神经动员中起着重要作用。此外，ORX 1受体拮抗剂可能是一种治疗选择，可快速治疗惊恐发作期间和高碳酸血症状态（如CORD）中出现的焦虑和交感神经冲动增加。
Acute hypercapnia (elevated arterial CO2/H+) is a suffocation signal that is life threatening and rapidly mobilizes adaptive changes in breathing and behavioral arousal in order to restore acid-base homeostasis. Severe hypercapnia, seen in respiratory disorders (eg, asthma or bronchitis, chronic obstructive pulmonary disease (COPD)), also results in high anxiety and autonomic activation. Recent evidence has demonstrated that wake-promoting hypothalamic brexin (ORX: also known as hypocretin) neurons are highly sensitive to local changes in CO2/H+, and mice lacking prepro-ORX have blunted respiratory responses to hypercapnia. Furthermore, in a recent clinical study, ORX-A, which crosses blood brain barrier easily, was dramatically increased in the plasma of patients with COPD and hypercapnic respiratory failure. This is consistent with a rodent model of CORD where chronic exposure to cigarette smoke led to a threefold increase in hypothalamic ORX-A expression. In the present study, we determined the role of ORX in the anxiety-like behavior and cardiorespiratory responses to acute exposure to a threshold panic challenge (ie, 20% CO2/normoxic gas). Exposing conscious rats to such hypercapnic, but not atmospheric air, resulted in respiratory, pressor, and bradycardic responses, as well as anxiety-like behavior and increased cellular c-Fos responses in ORX neurons. Systemically, pre-treating rats with a centrally active ORX1 receptor antagonist (30 mg/kg SB334867) attenuated hypercapnic gas-induced pressor and anxiety responses, without altering the robust bradycardia response, and only attenuated breathing responses at offset of the CO2 challenge. Our results show that the ORX system has an important role in anxiety and sympathetic mobilization during hypercapnia. Furthermore, ORX1 receptor antagonists may be a therapeutic option rapidly treating increased anxiety and sympathetic drive seen during panic attacks and in hypercapnic states such as CORD.