PDF(Pubmed)
Abstract：
Orexin-mediated stimulation of orexin receptors 1/2 (OX[1/2]R) may stimulate the diaphragm and genioglossus muscle via activation of inspiratory neurons in the pre-Bötzinger complex, which are critical for the generation of inspiratory rhythm, and phrenic and hypoglossal motoneurons. Herein, we assessed the effects of OX2R-selective agonists TAK-925 (danavorexton) and OX-201 on respiratory function. In in vitro electrophysiologic analyses using rat medullary slices, danavorexton and OX-201 showed tendency and significant effect, respectively, in increasing the frequency of inspiratory synaptic currents of inspiratory neurons in the pre-Bötzinger complex. In rat medullary slices, both danavorexton and OX-201 significantly increased the frequency of inspiratory synaptic currents of hypoglossal motoneurons. Danavorexton and OX-201 also showed significant effect and tendency, respectively, in increasing the frequency of burst activity recorded from the cervical (C3-C5) ventral root, which contains axons of phrenic motoneurons, in in vitro electrophysiologic analyses from rat isolated brainstem-spinal cord preparations. Electromyogram recordings revealed that intravenous administration of OX-201 increased burst frequency of the diaphragm and burst amplitude of the genioglossus muscle in isoflurane- and urethane-anesthetized rats, respectively. In whole-body plethysmography analyses, oral administration of OX-201 increased respiratory activity in free-moving mice. Overall, these results suggest that OX2R-selective agonists enhance respiratory function via activation of the diaphragm and genioglossus muscle through stimulation of inspiratory neurons in the pre-Bötzinger complex, and phrenic and hypoglossal motoneurons. OX2R-selective agonists could be promising drugs for various conditions with respiratory dysfunction.
摘要：
食欲素介导的食欲素受体1/2（OX[1/2]R）的刺激可能通过激活前Bötzinger复合体中的吸气神经元来刺激diaphragm肌和the舌肌，这对吸气节律的产生至关重要，膈和舌下神经运动神经元.在这里，我们评估了OX2R选择性激动剂TAK-925(danavorexton)和OX-201对呼吸功能的影响.在使用大鼠髓质切片的体外电生理分析中，danavorexton和OX-201显示出趋势和显着的效果，分别,增加前Bötzinger复合体中吸气神经元的吸气突触电流的频率。在大鼠髓质切片中，danavorexton和OX-201均显着增加了舌下神经运动神经元的吸气突触电流的频率。Danavorexton和OX-201也显示出显著的效果和趋势，分别,在增加从子宫颈（C3-C5）腹根记录的爆发活动的频率，包含膈运动神经元的轴突，从大鼠分离的脑干脊髓制剂进行体外电生理分析。肌电图记录显示，静脉注射OX-201可增加异氟烷和氨基甲酸乙酯麻醉的大鼠的the肌爆发频率和the肌爆发幅度，分别。在全身体积描记术分析中，口服OX-201可增加自由移动小鼠的呼吸活动。总的来说,这些结果表明，OX2R-选择性激动剂通过刺激前Bötzinger复合物中的吸气神经元，通过激活diaphragm肌和the舌肌增强呼吸功能，膈和舌下神经运动神经元.OX2R选择性激动剂可能是治疗各种呼吸功能障碍的有希望的药物。
