Breath-taking complexity of vagal C-fibre nociceptors: implications for inflammatory pulmonary disease, dyspnoea and cough


  • Dirk Adriaensen,

    1. Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Groenenborgerlaan 171, BE-2020 Antwerp, Belgium
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  • Jean-Pierre Timmermans

    1. Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Groenenborgerlaan 171, BE-2020 Antwerp, Belgium
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Vagal sensory nerves are traditionally considered as the afferent pathways that detect physiological information from visceral organs, including airways and lungs, while spinal afferents are involved in the detection of ‘noxious’ information. More recently, however, subsets of vagal afferents have also been implicated in processing potentially harmful stimuli (nociceptors) (Kollarik et al. 2010).

Recent reviews describe at least seven electrophysiologically characterized vagal sensory airway receptors, including slowly adapting receptors (SARs), rapidly adapting receptors (RARs), bronchial and pulmonary C-fibre receptors (CFRs), high threshold Aδ-receptors (HTARs), cough receptors and neuroepithelial bodies (NEBs) (Adriaensen et al. 2006; Widdicombe, 2009; Yu, 2009). Similarly, many respiratory sensations have been reported (pain/ache, irritation, tightness, urge-to-cough, air-hunger, sense of effort, sense of lung volume/airflow, temperature sense, etc.). The often reported ‘dyspnoea’ or its near equivalent ‘breathlessness’ includes air-hunger, sense of effort and tightness. Several of these sensations unmistakably originate from the lungs and lower respiratory tract but, unfortunately, hard evidence for these sensations being evoked by any of the airway sensors is still lacking (Widdicombe, 2009). Both HTARs, connecting to thin myelinated fibres, and CFRs, linked to non-myelinated fibres, are considered as subgroups of vagal airway nociceptors (Yu et al. 2007; Yu, 2009).

In a recent issue of The Journal of Physiology, Nassenstein et al. (2010) deal with the detailed characterization of putative nociceptive vagal sensors in mouse lungs, with special focus on bronchopulmonary CFRs. C-fibres, which comprise a majority of the vagal airway afferents, innervate multiple targets over the entire respiratory tract and project to the nucleus of the solitary tract. Their activity is now believed to play important roles in the physiological regulation of cardiopulmonary function (Lee, 2009). Vagal CFRs are quiescent in healthy lungs but are readily activated by noxious chemicals, including cigarette smoke and inflammatory mediators (Kollarik et al. 2010; Lee et al. 2010). Activation of CFRs either by chemical irritants or by physiological stress may elicit a variety of pronounced respiratory and cardiovascular reflex responses, such as airway constriction, mucous secretion, cough, tachypnea, hypotension, chemotaxis of inflammatory cells, etc. These responses are mediated through both central and peripheral reflex pathways. The huge variability probably reflects both the nature of the stimulus and the possibility that several CFR subtypes may be involved (Lee, 2009).

Recent evidence strongly suggests that CFRs and HTARs also play a crucial role in neuroimmune interactions and that the sensitivity of bronchopulmonary C-fibres can be markedly elevated in inflammatory airway disease, likely to be caused by the sensitizing effect of inflammatory mediators (Yu et al. 2007; Lee, 2009; Undem & Nassenstein, 2009; Yu, 2009). Airway sensory activation may cause local neurogenic inflammation, or can initiate responses via the vagus nerve. CFRs could be regarded as biosensors that monitor the inflammatory status of the lungs by directly interacting with inflammatory mediators/modulators (Yu et al. 2007; Yu, 2009).

A variety of dyspnoeic events are typically related to inflammatory airway disorders such as asthma and obstructive airway disease. Although the neurobiology of dyspnoea is complex, there is little doubt that bronchopulmonary vagal nerves play a causative and/or modulating role in dyspnoeic sensations, which will be exaggerated in inflammatory airway disease (Undem & Nassenstein, 2009). Evidence has accumulated that CFRs are involved in the genesis of dyspnoea and that blockade of vagal C-fibres attenuates the dyspnoeic response to chemical stimuli (Lee, 2009; Burki & Lee, 2010).

‘Urge-to-cough’ is one of the common respiratory discomforts and symptoms found in airway disease patients (Lee, 2009). Today, data support the hypothesis that at least two vagal nerve populations are responsible for initiating cough reflexes, one of them being a C-fibre population. Inhalation of selective CFR stimulants leads to cough only in conscious animals and humans. When more complete information on their neurochemical and molecular nature becomes available, targeting of vagal CFRs for novel antitussive therapy is certainly promising (Undem & Carr, 2010).

Altogether, our fundamental understanding of the vagal nociceptors involved in detecting and transmitting vital information for breathing control and regulation of immune responses remains incomplete in many respects (exact location, morphological, molecular and neurochemical characteristics, activation and reflex mechanisms, match with respiratory sensations, etc.). Obviously, new information will be pivotal to assess the roles of these receptors in respiratory physiology and pathology.

In line with the need for a more accurate CFR classification, including so far unavailable molecular information, the article by Nassenstein et al. comprises a meticulously performed analysis of the many (sub) types of vagal bronchopulmonary capsaicin-sensitive nociceptors. The authors provide an unambiguous view of the presence and detailed location of vagal jugular (neural crest derived) and vagal nodose (epibranchial placode derived) sensory neurons, in mice joined in a single ganglion but retaining specific locations. The electrophysiological characteristics and activation patterns were studied in an elegant innervated isolated ex vivo mouse trachea–lung preparation. The molecular characterization, using single-cell RT-PCR, of neurons that were individually characterized by retrograde tracing from the airways, led to the differentiation of a multitude of phenotypes of capsaicin-sensitive lung-projecting C-fibre neurons that fit into two major groups that coincide with their embryonic origin. The hypothesis was put forward that bronchopulmonary CFRs that are accessible to stimuli from the external environment (‘extero-receptors’) are mainly neural crest derived, whereas those terminating deeper within the lung tissue (‘intero-receptors’) are more placodal in nature. The selective but variable expression of neurotrophic factor receptors suggests that the phenotypic neuromodulation reported in inflammatory airway disease may depend on the subtype and location of the C-fibre terminals. Interestingly, the considerable neurochemical and molecular variety of these nociceptors may hold the key for the observed variability in sensations evoked by peripheral stimulation of the bronchopulmonary receptor terminals.