Marian Kollarik & Bradley J Undem
The Johns Hopkins School of Medicine, Baltimore, MD, USA

https://doi.org/10.36866/pn.62.31

In his timeless text on the integrated action of the nervous system, Sherrington discussed specific types of sensory nerve fibres in the skin that ‘Instead of but one kind of stimulus being their adequate excitant, they may be regarded as adapted to a whole group of excitants, a group of excitants which has in relations to the organism one feature common to all its components, namely a nocuous character’ (Sherrington, 1906). He reasoned that such nerve fibres ‘under selective adaptation, attach to the skin a so-to-say specific sense of its own injuries’. The term given to this special type of afferent nerve is nociceptor. It naturally would be useful for the organism if organs other than the skin also have a ‘specific sense of their own injuries’, and indeed nociceptors have been identified in virtually every visceral tissue. In modern usage the term ‘nociceptor’ is often, explicitly or implicitly, narrowed to include only sensory nerves that mediate pain. This change in characterizing nociceptors, from the nature of their activators to the consequences of their activation, has a major influence on the type of afferent nerves that are categorized as nociceptors. It is unknown at this time whether stimulation of any type of vagal afferent nerve in the oesophagus can overtly lead to pain, yet it would seem clear that there are vagal afferent nerves that can be accurately characterized as nociceptors. Our recent studies have served to add support for this contention (Yu et al. 2005).

It has long been recognized that airways and lungs receive large numbers of vagal afferent C-fibres (often termed bronchopulmonary C­fibres) (Coleridge & Coleridge, 1984). These nerves nicely fit into Sherrington’s definition of nociceptors. They are quiet during normal activity of the respiratory system but respond vigorously to a long list of noxious stimuli with, again using Sherrington’s words, ‘the common feature of having a nocuous character’. These stimuli include noxious airborne irritants, inflammatory mediators, and excessive tissue distension. The bronchopulmonary C-fibres, like the somatosensory nociceptors in skin, express the capsaicin receptor TRPV1, rendering them also sensitive to a variety of noxious chemical stimuli including vanilloids and acid. In addition, although bronchopulmonary nociceptors may not mediate pain, their activation has been associated with unpleasant sensations such as dyspnoea and can lead directly to protective reflexes that include apnoea, cough and mucus hypersecretion (Coleridge & Coleridge, 1984).

Textbooks and review articles often associate vagal afferent nerves in the oesophagus exclusively with the autonomic regulation of homeostasis. This implies that the afferent nerves designed to respond to actual or impending tissue damage are limited to the spinal nerves with their cell bodies in the dorsal root ganglia. This hypothesis finds credence in studies where few, if any, vagal sensory nerve fibres in the oesophagus had characteristics consistent with nociceptors (e.g. Sengupta et al. 1989).

It has been recognized that noxious stimuli in oesophagus can amplify vagal reflexes such as cough. This and certain similarities in the pattern of the vagal innervation between lungs and oesophagus led us to hypothesize that the vagus supplies nociceptors to the oesophagus in a fashion similar to the bronchopulmonary C-fibres in the neighboring respiratory tract. Our recent paper experimentally addresses this hypothesis in guinea pigs (Yu et al. 2005).

We found that the guinea pig oesophagus is indeed supplied by a large population of vagal nociceptors. In fact, based on functional and histological assessment, nociceptive nerves may represent the predominant type of vagal afferent nerve in the oesophagus. The vagal nociceptors are readily distinguishable from vagal non­nociceptive low threshold mechanosensors (also termed tension receptors). Like spinal nociceptors, but unlike vagal tension receptors, vagal nociceptors discriminate noxious distension of the oesophagus (Fig. 1) and they express the TRPV1 receptor that confers sensitivity to variety of noxious chemical stimuli. Moreover, we found that vagal nociceptors in the oesophagus are not a homogeneous population, but can be divided into two groups based on their embryonic origin. Nociceptors derived from the embryonic placodes, whose cell bodies are situated in the vagal nodose ganglia, can be activated by a broad spectrum of autacoids, including 5-HT, ATP, and adenosine. Oesophageal vagal nociceptors derived from the neural crest, whose cell bodies are located in vagal jugular (supranodose) ganglia, are rather unresponsive to these autacoids. Placodes- and neural crest-derived vagal oesophageal nociceptors also differ in their expression of neurokinin peptides. The spinal afferent nerves innervating the oesophagus, many of which are nociceptors, also originate from neural crest. Based on some preliminary data, we speculate that their phenotype will prove to be more similar to jugular than to nodose vagal nociceptors.

Although it seems clear that the vagus nerves innervating the oesophagus comprise large numbers of nociceptors, the consequence of their activation is less clear. It can be reasoned that these nerves should cause effects consistent with the oesophagus ‘being informed of its own injury’. Some recent work indicates that vagal afferent fibres are required for aversive responses to noxious gastric stimulation in the rat (Lamb et al. 2003). There has been speculation that vagal nociceptors may contribute to the emotional components that accompany pain perceptions (Berthoud & Neuhuber 2000). It is also likely that vagal nociceptors may serve to coordinate defensive reflexes aimed at diluting or ridding the tissue of the potential noxious stimuli.

References

Berthoud HR & Neuhuber WL (2000). Functional and chemical anatomy of the afferent vagal system. Auton Neurosci 85, 1-17.

Coleridge JC & Coleridge HM (1984). Afferent vagal C fibre innervation of the lungs and airways and its functional significance. Rev Physiol Biochem Pharmacol 99, 1-110.

Lamb K, Kang YM, Gebhart GF & Bielefeldt K (2003). Gastric inflammation triggers hypersensitivity to acid in awake rats. Gastroenterology 125, 1410-1418.

Sengupta JN, Kauvar D & Goyal RK (1989). Characteristics of vagal esophageal tension-sensitive afferent fibers in the opossum. J Neurophysiol 61, 1001-1010.

Sherrington SC (1906). The integrative action of the nervous system. Yale University Press, New Haven.

Yu S, Undem BJ & Kollarik M (2005). Vagal afferent nerves with nociceptive properties in guinea-pig oesophagus. J Physiol 563, 831-842.