Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, 3010, Australia.
Department of Medical Imaging and Radiation Sciences, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
J Physiol. 2020 Jun;598(11):2257-2275. doi: 10.1113/JP279644. Epub 2020 May 1.
Airway projecting sensory neurons arising from the jugular vagal ganglia terminate centrally in the brainstem paratrigeminal nucleus, synapsing upon neurons expressing the neurokinin 1 receptor. This study aimed to assess the involvement of paratrigeminal neurokinin 1 receptor neurons in the regulation of cough, breathing and airway defensive responses. Lesioning neurokinin 1 receptor expressing paratrigeminal neurons significantly reduced cough evoked by inhaled bradykinin but not inhaled ATP or tracheal mechanical stimulation. The reduction in bradykinin-evoked cough was not accompanied by changes in baseline or evoked respiratory variables (e.g. frequency, volume or timing), animal avoidance behaviours or the laryngeal apnoea reflex. These findings warrant further investigations into targeting the jugular ganglia and paratrigeminal nucleus as a therapy for treating cough in disease.
Jugular vagal ganglia sensory neurons innervate the large airways and are thought to mediate cough and associated perceptions of airway irritations to a range of chemical irritants. The central terminals of jugular sensory neurons lie within the brainstem paratrigeminal nucleus, where postsynaptic neurons can be differentiated based on the absence or presence of the neurokinin 1 (NK1) receptor. Therefore, in the present study, we set out to test the hypothesis that NK1 receptor expressing paratrigeminal neurons play a role in cough evoked by inhaled chemical irritants. To test this, we performed selective neurotoxin lesions of NK1 receptor expressing neurons in the paratrigeminal nucleus in guinea-pigs using substance P conjugated to saporin (SSP-SAP). Sham lesion control or SSP-SAP lesion guinea-pigs received nebulised challenges, with the pan-nociceptor stimulant bradykinin or the nodose ganglia specific stimulant adenosine 5'-triphosphate (ATP), in conscious whole-body plethysmography to study cough and associated behaviours. Laryngeal apnoea reflexes and cough evoked by mechanical stimulation of the trachea were additionally investigated in anaesthetised guinea-pigs. SSP-SAP significantly and selectively reduced the number of NK1 receptor expressing neurons in the paratrigeminal nucleus. This was associated with a significant reduction in bradykinin-evoked cough, but not ATP-evoked cough, mechanical cough or laryngeal apnoeic responses. These data provide further evidence for a role of jugular vagal pathways in cough, and additionally suggest an involvement of NK1 receptor expressing neurons in the paratrigeminal nucleus. Therefore, this neural pathway may provide novel therapeutic opportunities to treat conditions of chronic cough.
起源于颈静脉神经节的气道投射感觉神经元在脑干三叉神经脊束核内中枢终止，与表达神经激肽 1 受体的神经元形成突触。本研究旨在评估三叉神经脊束核神经激肽 1 受体神经元在调节咳嗽、呼吸和气道防御反应中的作用。损伤表达神经激肽 1 受体的三叉神经脊束核神经元可显著减少吸入缓激肽引起的咳嗽，但不减少吸入 ATP 或气管机械刺激引起的咳嗽。缓激肽诱发的咳嗽减少与基线或诱发的呼吸变量（如频率、体积或时间）、动物回避行为或喉呼吸暂停反射无变化有关。这些发现进一步证明，靶向颈静脉神经节和三叉神经脊束核作为治疗疾病性咳嗽的一种治疗方法是合理的。
颈静脉神经节感觉神经元支配大气道，被认为介导咳嗽和对多种化学刺激物的气道刺激相关感知。颈静脉感觉神经元的中枢末端位于脑干三叉神经脊束核内，根据神经激肽 1（NK1）受体的存在或不存在，可以区分突触后神经元。因此，在本研究中，我们着手测试 NK1 受体表达的三叉神经脊束核神经元在吸入化学刺激物引起的咳嗽中的作用的假设。为此，我们使用 P 物质偶联的苦毒蕈碱（SSP-SAP）对豚鼠三叉神经脊束核中的 NK1 受体表达神经元进行选择性神经毒素损伤。假损伤对照或 SSP-SAP 损伤豚鼠在清醒全身 plethysmography 中接受雾化挑战，用泛伤害感受器刺激剂缓激肽或结状神经节特异性刺激剂三磷酸腺苷（ATP）进行研究，以研究咳嗽和相关行为。此外，还在麻醉豚鼠中研究了气管机械刺激引起的喉呼吸暂停反射和咳嗽。SSP-SAP 显著且选择性地减少了三叉神经脊束核中 NK1 受体表达神经元的数量。这与缓激肽诱发的咳嗽显著减少有关，但与 ATP 诱发的咳嗽、机械性咳嗽或喉呼吸暂停反应无关。这些数据进一步证明了颈静脉迷走神经通路在咳嗽中的作用，并提示三叉神经脊束核中 NK1 受体表达神经元的参与。因此，该神经通路可能为治疗慢性咳嗽等疾病提供新的治疗机会。
