Regulation of the Cough Reflex

描述(申请人提供)：咳嗽是美国病人去看医生的最常见原因。这项研究的长期目标是描绘咳嗽产生和调节的神经发生机制。这项研究的中心假设是咳嗽运动模式是由一组组件产生的，该组件包括一个新的调节元件，负责控制重新配置的呼吸模式生成器的行为。此外，控制喉部和气管支气管部咳嗽的新的调节成分并不相同。这项研究的基本原理是，一旦建立了脑干咳嗽模式产生系统的功能组织，就可以确定病理性咳嗽产生的机制。该项目的具体目标是：1)确定呼气相的调制在调节气管、支气管和喉部咳嗽运动模式中的作用；2)确定气管、支气管和喉部咳嗽的中枢调节系统的功能组织；3)确定脑干呼气运动通路在气管、支气管咳嗽的止咳敏感调节系统中的作用；4)确定脊髓呼气运动通路在咳嗽止咳敏感调节系统中的作用。在第一个目标中，控制反复气管、支气管和喉部咳嗽的频率和幅度的关键调节机制将通过改变各自的兴奋性来确定。我们的初步数据表明，a)重复咳嗽的频率主要由咳嗽呼气期后期持续时间的调节来控制，以及b)重复咳嗽的频率和强度的控制是由单独的调节机制负责的。为了支持第二个目标，初步研究结果表明，气管、支气管部和喉部咳嗽对镇咳药物的敏感性不同，因此每种药物的中枢调节机制也不同。在第三个目标中，我们测试了一个模型，该模型预测了气管、支气管咳嗽门控机制的存在，该机制是与延髓和脊髓呼气运动通路的突触前相联系的。这种门控机制对镇咳药物很敏感。在呼吸和咳嗽时，将测定延髓头端和尾端延髓呼气神经元对镇咳药物的敏感性，以区分这些化合物对这些神经元的抑制或障碍。在第四个目标中，将在监测咳嗽时呼气运动驱动的同时鞘内注射镇咳药物，以确定脊髓通路在抑制呼气运动放电中的作用。这些实验的结果将为所提出的咳嗽模式生成器的功能组织提供重要的测试。此外，该项目还将测试延髓和脊髓细胞成分对咳嗽时呼气运动放电的产生和控制所起的作用。

DESCRIPTION (provided by applicant): Cough is the most common reason why sick patients visit physicians in the US. The long-range goal of this research is to delineate the neurogenic mechanisms by which cough is produced and regulated. The central hypothesis of this research is that the cough motor pattern is produced by an assembly of components that includes a novel regulatory element responsible for controlling the behavior of a reconfigured respiratory pattern generator. Moreover, the novel regulatory components that control laryngeal and tracheobronchial cough are not identical. The rationale for the proposed research is that once the functional organization of the brainstem cough pattern generation system is established, the mechanisms responsible for the production of pathological cough can be identified. The specific aims of the project are: 1) Determine the role of modulation of the expiratory phase in the regulation of the tracheobronchial and laryngeal cough motor patterns, 2) Determine the functional organization of the central regulatory system for tracheobronchial and laryngeal cough, 3) Determine the role of brainstem expiratory motor pathways in the antitussive-sensitive regulatory system for tracheobronchial cough, 4) Determine the role of spinal expiratory motor pathways in the antitussive-sensitive regulatory system for cough. In the first aim, key regulatory mechanisms controlling the frequency and magnitude of repetitive tracheobronchial and laryngeal cough will be determined by altering of the excitability of each. Our preliminary data suggest a) that the frequency of repetitive coughing is primarily controlled by modulation of the duration of the latter part of the cough expiratory phase, and b) that separate regulatory mechanisms are responsible for the control of the frequency and intensity of repetitive coughing. In support of the second aim, preliminary findings suggest differential sensitivity of tracheobronchial and laryngeal cough to antitussive drugs and thus divergent central regulatory mechanisms for each. In the third aim, we test a model that predicts the presence of a tracheobronchial cough gating mechanism that is presynaptic to medullary and spinal expiratory motor pathways. This gating mechanism is sensitive to antitussive drugs. The sensitivity of rostral and caudal medullary expiratory neurons to antitussive drugs will be determined during breathing and cough to differentiate between inhibition or disfacilitation of these neurons by these compounds. In the fourth aim, antitussive drugs will be delivered intrathecally while monitoring expiratory motor drive during cough to determine the role of spinal pathways in the suppression of expiratory motor discharge. The results of these experiments will provide an important test of the proposed functional organization of the cough pattern generator. Furthermore, this project will test the proposed roles of medullary and spinal cellular elements that contribute to the generation and control of expiratory motor discharge during cough.