Regulation of the Cough Reflex

描述（由申请人提供）：咳嗽是美国病人就诊最常见的原因。本研究的长期目标是描述咳嗽产生和调节的神经源性机制。本研究的中心假设是咳嗽运动模式是由一系列组件产生的，其中包括一个负责控制重新配置的呼吸模式发生器行为的新调节元件。此外，控制喉部和气管支气管咳嗽的新调控成分并不相同。本研究的基本原理是，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)确定呼气期调节在气管支气管和喉部咳嗽运动模式调节中的作用，2)确定气管支气管和喉部咳嗽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抗咳敏感调节系统中的作用。4)确定脊髓呼气运动通路在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频率和强度的关键调节机制将通过改变它们的兴奋性来确定。我们的初步数据表明：a)反复咳嗽的频率主要由咳嗽呼气期后期持续时间的调节控制；b)反复咳嗽的频率和强度的控制由不同的调节机制负责。为了支持第二个目的，初步研究结果表明，气管、支气管和喉部咳嗽对止咳药物的敏感性不同，因此它们的中枢调节机制不同。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，该机制是突触前到髓质和脊髓呼气运动通路。这种门控机制对止咳药物敏感。在呼吸和咳嗽过程中测定吻侧和尾侧髓质呼气神经元对止咳药物的敏感性，以区分这些化合物对这些神经元的抑制或阻碍作用。在第四个目的中，在监测咳嗽过程中呼气运动驱动的同时，鞘内给予止咳药物，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提出的咳嗽模式发生器的功能组织提供重要的测试。此外，本项目将测试在咳嗽过程中产生和控制呼气运动放电的髓细胞和脊髓细胞成分的作用。

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.