Vague no more: Evidence of divergent central pathways of sensory nerves innervating the human airways

The Xth cranial nerve is called the vagus nerve, derived from the Latin word for wandering, as a result of its rambling projection from the vagal ganglia just outside the brainstem to visceral organs within the thorax and abdomen. The vagus provides afferent (e.g. sensory) and efferent (i.e. parasympathetic and branchiomotor) innervation to visceral organs and is critical for their homeostatic and defensive regulation. Vagal afferents are heterogenous with respect to gene expression, connectivity and function, although some phenotypic differences are a result of embryological origin (Mazzone & Undem, 2016). Vagal ganglia comprise a complex of the nodose ganglion and the jugular ganglion, and soma found in these distinct ganglia are derived selectively from the epibranchial placodes and the neural crest, respectively. Functional differences between nodose and jugular sensory pathways have been most clearly demonstrated in the regulation of respiratory reflexes in guinea pigs, where activation of airway defensive (i.e. nociceptive) afferents caused either stimulation or inhibition of the cough reflex depending on whether jugular or nodose afferents were stimulated. Recently, tracing studies in rodents have shown that, in addition to the well-characterized central pathway of vagal afferents to the nucleus tractus solitarius (nTS) in the dorsomedial medulla, some vagal afferents terminate in the paratrigeminal complex (Pa5) in the dorsolateral medulla (Driessen et al. 2018). Evidence suggests this is a preferential pathway of jugular nociceptors and is critical to the central processing of respiratory reflexes. In this issue of The Journal of Physiology, Farrell et al (2020) report the first evidence indicating that signalling evoked by stimulants of vagal nociceptors innervating the respiratory tract activates central pathways in both the nTS and Pa5 of conscious human subjects. Using functional magnetic resonance imaging (fMRI) of the brainstem and brain during inhalation of capsaicin, which activates all airway nociceptors, as well as ATP, which only activates airway nodose nociceptors, Farrell et al (2020) demonstrate that the selective connectivity of vagal afferents observed in animal studies also occurs in humans: that airway nodose pathways project to the nTS, whereas jugular pathways input into the Pa5. The study also shows that the efficacy of evoking cough positively correlated with Pa5 activation, consistent with animal studies. The study by Farrell et al (2020) therefore provides the first evidence indicating that the Pa5 represents a novel ‘cough centre’ in humans, thus spurring further research in elucidating details of its poorly understood function. Cough, regardless of whether it is a result of asthma, bronchitis, gastroesophageal reflux and infections or is idiopathic, is the most common reason for seeking primary care, and is largely resistant to current pharmaceutical therapies. Targeting the afferent pathways involved in cough, either with drugs or electroceuticals, may well be successful, although this requires a detailed understanding of the pathways and mechanisms involved. Other debilitating respiratory symptoms also have a neuronal component. For example, afferents have been implicated in reflex bronchospasm, wheeze and airway hyperreactivity in asthma (Trankner et al. 2014; Mazzone & Undem, 2016). Whether the jugular-Pa5 pathway contributes to these responses remains to be investigated. One great and unique advantage of human studies is the ability to measure perception in addition to physiological function. Here, Farrell et al (2020) have shown that, perhaps surprisingly given the lack of efficacy in evoking cough, ATP nonetheless evoked an urge-to-cough sensation. Although it remains to be demonstrated that the quality of urge-to-cough sensations evoked by capsaicin and ATP is different, this unexpected complexity suggests precision is required for future neuromodulation therapies. There are three caveats to their study. First, blood oxygenation level-dependent (BOLD) responses measured in high-resolution fMRI do not offer the pinpoint resolution of neural mapping that is possible with connectome tracing in animal models. Thus, identifying activated CNS subnuclei has its limitations. Second, no jugular nociceptor-specific stimulus was used. Instead subtraction of ATP-evoked signals from capsaicin-evoked signals was used to determine the jugular response. Lastly, inhalation of irritants also may stimulate facial trigeminal afferents. Previous studies by the group indicated that oropharyngeal and airway responses can be temporally distinguished (Mazzone et al. 2007). Nevertheless, the study by Farrell et al (2020) presents compelling evidence indicating that the jugular-Pa5 pathway is functionally relevant in human subjects. Whether this pathway is only involved in airway protection or whether it also contributes to the regulation of other thoracic organs is currently unknown. No competing interests declared. Both authors contributed equally. This work was funded by the National Institutes of Health Office of the Director's Stimulating Peripheral Activity to Relieve Conditions (SPARC) program (OT2OD023854) and the National Institute of Neurological Disorders and Stroke (U01NS113868).