Neurophysiology of the cough reflex.
Neurophysiology of the cough reflex.
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咳嗽反射的神经生理学。
DOI：
10.1183/09031936.96.09030621
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
J. Karlsson
中科院分区：
文献类型：
--
作者：
R. Fuller;L. Hansson;J. Karlsson
我们怀着极大的兴趣阅读了WIDDICOMBE最近发表在《华尔街日报》7月号上的综述《咳嗽反射的神经生理学》[1]。该综述详细介绍了气道中的传入神经，特别是那些可能直接或间接参与咳嗽反射的神经。主要基于猫和狗中触发感觉神经电活动和咳嗽的选定刺激物的数据，作者得出结论，薄的、有髓鞘的、快速适应的牵张受体（RAR），“刺激受体”，独特地介导咳嗽反射，并且肺C纤维抑制咳嗽。在我们看来，已发表的豚鼠和人的实验数据表明RAR和支气管C纤维在介导咳嗽反射方面都很重要。以下观察结果支持支气管C纤维在咳嗽中的直接作用。首先，与RAR和缓慢适应牵张受体（SAR）相比，辣椒素是C纤维的相对选择性刺激。当清醒的豚鼠和人类受试者吸入低剂量的辣椒素时会引发咳嗽。来自豚鼠气管支气管制备物的传入神经活动的电生理学记录表明，辣椒素刺激C纤维，但不刺激A-δ纤维（RAR）[2]。辣椒素也是一种比猫[3]和狗[4]中的RAR更有效的C纤维刺激剂。重要的是，辣椒素引起C纤维的活动爆发，而C纤维通常是沉默的，而辣椒素只是增强了有髓鞘纤维中预先存在的自发放电[3，4]。其次，辣椒素预处理豚鼠（导致化学敏感的Cfibre传入群体退化）抑制辣椒素和柠檬酸引起的咳嗽，但不抑制香烟烟雾、组胺和机械刺激引起的咳嗽，表明不同类型的传入神经可以直接介导这种反射[5]。有趣的是，尼古丁和组胺已被证明可刺激豚鼠的RAR [6]。第三，豚鼠长期暴露于香烟烟雾选择性地增强介导咳嗽的辣椒素敏感C纤维的敏感性，并增加气道神经的神经肽含量，同时使支气管收缩反应不受影响[7]。与此同时，对香烟烟雾的咳嗽反应没有改变，这表明辣椒素敏感的C纤维的选择性上调。第四，虽然辣椒素通过轴突反射从C纤维释放速激肽和降钙素基因相关肽（CGRP），但它们不太可能激活气道RAR，从而间接触发咳嗽反射。吸入速激肽肽不会引起健康受试者咳嗽[8]，并且当人类受试者吸入thiorphan（一种速激肽的中性内肽酶代谢抑制剂）时，据报道仅增强了对神经激肽A的支气管收缩反应[9]。类似地，在豚鼠中，我们发现thiorphan增强了柠檬酸诱导的支气管痉挛，但没有增强咳嗽反应[10]。一项研究报告，噻喃可增强对P物质（SP）的咳嗽反应，但该发现的意义难以评估，因为研究的SP浓度非常低（10-19至10-16 M），在2分钟气雾剂暴露后13分钟内测量到咳嗽，乙醇溶剂也引起咳嗽[11]。最近显示，神经激肽-1（NK 1）受体拮抗剂不能抑制哮喘受试者高渗盐水诱导的咳嗽[12]。最后，豚鼠和人[13]支气管对吸入C纤维兴奋剂的咳嗽效应比喉和中央气道更敏感，这与无髓鞘支气管C纤维主要分布于肺内气道一致。肺化学反射是通过肺纤维介导的，其特征是呼吸暂停、心动过缓和低血压。如综述中所述，刺激这些纤维可抑制咳嗽，这仅在呼吸暂停期间中枢神经系统（CNS）中的呼吸节律发生器受到抑制时才可预期。此外，如果咳嗽反射是从呼吸性细支气管和肺泡诱发的，那么咳嗽反射当然不会有效地作为防御机制，而呼吸性细支气管和肺泡似乎是这些特定感觉神经末梢的部位。咳嗽是一个重要的临床问题，不仅在慢性咳嗽的受试者中，而且在哮喘中，因为它可以是疾病的早期，有时是唯一的迹象。我们同意WIDDICOMBE [1]的观点，即RAR介导咳嗽反射，肺C纤维可能具有抑制作用，但我们认为大量实验数据支持支气管C纤维在咳嗽中的直接作用。辣椒素敏感性支气管C纤维传入中的感觉高反应性是慢性咳嗽的特征性特征（参见[14]），因此，识别气道反射中的神经通路可能导致更好地理解气道疾病（包括哮喘）的病理生理学，以及开发更有效的治疗剂。
We read with much interest the recent review "Neurophysiology of the cough reflex" by WIDDICOMBE [1], which appeared in the July issue of the Journal. The review gave a detailed account of afferent nerves in the airways, with particular reference to those that may directly or indirectly be involved in the cough reflex. Based primarily on data with select irritants which trigger electrical activity in sensory nerves and cough in cats and dogs, the author concludes that thin, myelinated, rapidly adapting stretch receptors (RARs), "irritant receptors", uniquely mediate the cough reflex and that lung C-fibres suppress coughing. In our opinion, published experimental data in guineapig and man indicate instead that both RARs and bronchial C-fibres are important in mediating the cough reflex. The following observations support a direct role for bronchial C-fibres in cough. Firstly, capsaicin is a relatively selective stimulus of C-fibres compared with RARs and slowly adapting stretch receptors (SARs). Low doses of capsaicin trigger cough when inhaled by conscious guinea-pigs and human subjects. Electrophysiological recordings of afferent neural activity from a guinea-pig tracheobronchial preparation demonstrate that capsaicin stimulates C-fibres but not A-δ fibres (RARs) [2]. Capsaicin is also a more potent stimulant of C-fibres than RARs in the cat [3] and dog [4]. Importantly, capsaicin causes a burst of activity in Cfibres, which are normally silent, whereas it merely potentiates a pre-existing spontaneous discharge in myelinated fibres [3, 4]. Secondly, capsaicin-pretreatment of guinea-pigs (causing degeneration of a population of chemosensitive Cfibre afferents) inhibits coughing due to capsaicin and citric acid, but not that due to cigarette smoke, histamine and mechanical stimulation, indicating that different types of afferent nerves can directly mediate this reflex [5]. Interestingly, nicotine and histamine have been shown to stimulate RARs in guinea-pigs [6]. Thirdly, chronic exposure of guinea-pigs to cigarette smoke selectively enhances the sensitivity of capsaicin-sensitive C-fibres mediating cough, and increases the neuropeptide content of airway nerves, whilst leaving the bronchoconstrictor response unaffected [7]. At the same time, the cough response to cigarette smoke is unchanged, suggesting a selective upregulation of capsaicin-sensitive Cfibres. Fourthly, although capsaicin releases tachykinins and calcitonin gene-related peptide (CGRP) from C-fibres via an axon-reflex, it is unlikely that they activate airway RARs and, thereby, indirectly trigger the cough reflex. Inhaled tachykinin peptides do not cause cough in healthy subjects [8], and when thiorphan (an inhibitor of neutralendopeptidase metabolism of tachykinins) is inhaled by human subjects, reportedly only the bronchoconstrictor response to neurokinin A is enhanced [9]. Similarly, in guinea-pigs, we found that, thiorphan enhanced the citric acid-induced bronchospasm but not the cough response [10]. One study has reported that thiorphan potentiates the cough response to substance P (SP) but the significance of this finding is difficult to assess since very low concentrations of SP (10-19 to 10-16 M) were studied, coughing was measured up to 13 min after a 2 min aerosol exposure, and the ethanol vehicle also produced coughing [11]. It was recently shown that a neurokinin-1 (NK1)-receptor antagonist does not inhibit hypertonic saline-induced cough in asthmatic subjects [12]. Finally, guinea-pig and human [13] bronchi are more sensitive to the tussive effect of inhaled C-fibre stimulants than the larynx and central airways, which is consistent with the distribution of unmyelinated bronchial C-fibres predominantly to intrapulmonary airways. The pulmonary chemoreflex, characterized by apnoea, bradycardia and hypotension, is mediated via pulmonary Cfibres. As described in the review, stimulation of these fibres inhibits cough, which is only to be expected when the respiratory rhythm generator in the central nervous system (CNS) is suppressed during the apnoea. Furthermore, the cough reflex would of course not be effective as a defense mechanism if evoked from the respiratory bronchioles and alveoli, which seems to be the site of these particular sensory nerve endings. Cough is an important clinical problem, not only in subjects with chronic cough but also in asthma, since it can be an early, and sometimes the only, sign of disease. We agree with WIDDICOMBE [1] that RARs mediate the cough reflex and that pulmonary C-fibres may be inhibitory, but in our opinion a wealth of experimental data support a direct role for bronchial C-fibres in cough. Sensory hyperresponsiveness in capsaicin-sensitive bronchial C-fibre afferents is a characteristic feature of chronic cough (see [14]) and, inferentially, identification of neural pathways in airway reflexes may lead to a better understanding of the pathophysiology of airway diseases, including asthma, as well as to the development of more efficacious therapeutic agents.
L-薄荷醇对喉受体的影响。
DOI：
10.1152/jappl.1991.70.2.788
发表时间：
1991
期刊：
Journal of applied physiology (Bethesda, Md. : 1985)
影响因子：
--
作者：
Sant'Ambrogio,FB;Anderson,JW;Sant'Ambrogio,G
通讯作者：
Sant'Ambrogio,G
对辣椒素的反射反应：静脉注射、气雾剂和气管内给药。
DOI：
10.1152/jappl.1989.67.4.1428
发表时间：
1989
期刊：
Journal of applied physiology (Bethesda, Md. : 1985)
影响因子：
--
作者：
Palecek,F;Sant'Ambrogio,G;Sant'Ambrogio,FB;Mathew,OP
通讯作者：
Mathew,OP
中性肽链内切酶抑制剂可增强 P 物质和辣椒素引起的清醒豚鼠咳嗽。
DOI：
10.1172/jci113827
发表时间：
1988
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Kohrogi,H;Graf,PD;Sekizawa,K;Borson,DB;Nadel,JA
通讯作者：
Nadel,JA