Acid-sensitive vagal sensory pathways and cough

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Abstract

Acid is an important mediator in the pathogenesis of cough. Inhalation of exogenous acid triggers cough and endogenous acid may contribute to cough in respiratory diseases. Acid directly stimulates vagal bronchopulmonary sensory nerves that regulate the cough reflex. Consistent with their putative role in defence against aspiration and inhaled irritants, Aδ-fibre nociceptors in the large airways are most efficiently stimulated by rapid acidification. In contrast, acid-sensitive properties of the C-fibre nociceptors allow for continuous monitoring of pH which is likely important in inflammation. Acid is also the single most important mediator in the pathogenesis of cough due to gastro-oesophageal reflux (GOR). The cough pathways can be sensitized by the sensory inputs from the oesophagus. This sensitization is likely mediated by a subset of the vagal oesophageal sensory nerves distinguished by discriminative responsiveness to noxious stimuli (nociceptors). The receptors underlying acid sensitivity of vagal sensory nerves are incompletely understood. The role of TRPV1 has been established but the roles of acid-sensing ion channels (ASIC) and other receptors await more definitive investigation. Here, we provide a brief overview of the cough-related acid-sensitive sensory pathways and discuss the mechanisms of acid sensitivity.

Introduction

A decrease in local pH often accompanies inflammation, ischaemia or, in the gastrointestinal system, disorders of acid secretion and containment. Acid has multiple effects in tissues including activation of sensory nerves and/or modulation of sensory excitability. In this review, we discuss the effects of acid and the membrane ion channels underlying these effects in the sensory nerves regulating cough. We focus on the vagal sensory nerves in the airways, lungs and oesophagus, thought to be most important pathways mediating acid contribution to the pathogenesis of cough. We also aim to highlight some gaps in the current understanding of the sensory acid sensitivity and its mechanisms.

Section snippets

Peripheral sensory pathways regulating cough

The major pathways for triggering and/or modulation of cough are the vagal sensory nerves innervating the airways and lungs. The vagal innervation of these organs is described in detail elsewhere in this issue [1] and is only briefly outlined below. Another group of vagal afferent pathways important for the modulation of the cough reflex are the sensory nerves innervating the oesophagus. These pathways likely play a major role in the pathogenesis of cough due to gastro-oesophageal reflux (GOR),

Classification of vagal sensory nerves

Different classifications have been evolving to categorize sensory nerves in the respiratory and digestive systems [6], [7]. The criteria used to categorize the sensory nerves are typically based on their mechanical and chemical responsiveness, presumed location of the nerve terminals in the tissues and/or presumed reflex consequences of the nerve activation. For the purpose of this discussion, we adopt a broad classification of the sensory nerves into two categories: the low threshold

Vagal sensory innervation of the airways and lungs

Vagal low threshold mechanosensors in the lung comprise the classically described lung “stretch receptors” further subdivided into slowly and rapidly adapting receptors (SARs and RARs, respectively) based on the accommodation of the action potential discharge in response to sustained lung inflation. In all species studied thus far, the vagal low threshold mechanosensitive nerve fibres in the lung conduct action potentials in the A-fibre range (>10 m/s).

The vagal bronchopulmonary C-fibres are the

Vagal sensory innervation of the oesophagus

Vagal sensory nerves in the oesophagus are often associated only with the regulation of its physiological function and are thought not to directly participate in nociception (i.e. detection of noxious stimuli) [19]. This notion likely relates to the fact that the vagal sensory nerves with nociceptive properties were rarely reported in the oesophagus. Most studies of oesophageal sensory innervation focused on the non-nociceptive low threshold mechanosensors [10], [20], [21], [22]. However, more

Common pattern of the vagal innervation of the lungs and oesophagus in the guinea pig

The vagal sensory nerves are derived from two embryonic sources (reviewed in [29]). Sensory fibres that have neurones in the vagal nodose ganglia originate from the epibranchial placodes while sensory fibres that have neurones in the vagal jugular ganglia are derived from the neural crest. During their development and maturity, the nodose and jugular neurones also differ in their neurotrophin dependency. We have recently evaluated the hypothesis that the nodose and jugular neurones project

Acid in the tissue

Detailed discussion of acid production and turnover in different tissues under physiological and pathological circumstances is beyond the scope of this review. In general, the acid-producing pathways that can potentially lead to increased local concentrations of protons have been described. However, the degree of the acidification (pH) at the nerve terminals has not been measured. This is not only due to technical difficulties associated with such studies but also due to our incomplete

Acid-sensing mechanisms in sensory nerves

Only a few ion channels expressed in the primary sensory nerves are known to be directly gated by acid and lead to sensory activation. These include the capsaicin receptor TRPV1, certain other members of the transient receptor potential (TRP) superfamily (i.e. TRPV4), and acid-sensing ion channels (ASICs). The examples of the ion channels that are not directly gated, but are modulated by acid in a manner that can increase responsiveness of the sensory nerves include certain purinergic P2X

Effects of acid on the vagal sensory nerves

The pH deviation from the normal values indicates impeding or actual tissue damage and acid itself contributes to the tissue damage. Acid is therefore a prototypical noxious stimulus predicted to activate nociceptive nerves. Indeed, acid activates nociceptive nerves in the somatosensory system such as polymodal nociceptors in the skin [55]. Acid also evokes action potential discharge in the vagal nociceptive sensory nerves in the airways, lungs and oesophagus. In contrast to its stimulatory

Bronchopulmonary C-fibre nociceptors

Bronchopulmonary C-fibre nociceptors are effectively stimulated by acid in all species studied thus far: guinea pig [16], [56], rat [57] and mouse [58] (Fig. 3). The C-fibre nociceptors respond to the sustained acidic stimulus with a sustained action potential discharge. In the guinea pig, the pH threshold for acid-induced activation is about pH=6.0 [16], [56].

Using the only TRPV1 selective receptor antagonist available at that time, capsazepine, initial studies concluded that the TRPV1

Nociceptive “touch-sensitive” Aδ-fibres innervating large airways in the guinea pig

As discussed above, this special nociceptive sensory phenotype, which was extensively studied in the guinea pig, initiates immediate cough even in anaesthetized animals [17]. This nociceptive type is unique among the bronchopulmonary nociceptors in that it does not express the capsaicin receptor TRPV1. The “touch-sensitive” Aδ-fibres uniformly respond to the rapid acidification (a rapid drop in pH) at the tracheal epithelial surface with a robust action potential discharge [16]. Their threshold

Oesophageal nociceptors

Vagal oesophageal nociceptors nearly uniformly express the acid-sensitive TRPV1 receptors [23]. We found that nociceptors in the oesophagus are stimulated by acid. Fig. 2b shows the action potential discharge induced by acid (pH=5) in a nodose C-fibre nociceptor with the nerve terminal in the oesophagus. Whether TRPV1 is the sole receptor involved in this response is currently unknown.

Vagal low threshold mechanosensors in the oesophagus

The reports on the acid responsiveness of the vagal low threshold mechanosensors in the oesophagus are controversial. While some studies suggest that acid activates this nerve type in vivo in cats [26], others report little excitatory effect in ferrets in vivo [24] and in vitro in ferrets and mouse [23], [62]. We have recently addressed this issue in an ex vivo isolated innervated guinea pig oesophagus, a reduced system that allows for better control of indirect effects such as those due to

Spinal sensory innervation of the lungs and oesophagus

Although not the major focus of this review, the spinal sensory nerves originating in the neurones of spinal dorsal root ganglia (DRG) and projecting fibres to the lungs and oesophagus are worth discussing in the context of sensory responsiveness to acid and cough. Little is known of the roles of spinal sensory pathways as modulators of cough; however, there are well-established links between spinal sensory pathways and sensations. In this capacity, it is possible that the spinal pathways

Conclusions

Multiple pathways regulating cough are modulated by acid. Inhaled or aspirated acid, and acid generated in the respiratory system can stimulate bronchopulmonary nociceptors to trigger and/or sensitize cough. The ion channels involved in this stimulation are TRPV1 and most likely the ASICs, but the latter hypothesis still awaits more definitive studies. Acid refluxing from the stomach into the oesophagus can stimulate vagal nociceptive sensory nerves in the oesophagus. This can lead to cough by

References (71)

  • M. Tatar et al.

    The role of partial laryngeal denervation on the cough reflex in awake guinea-pigs, rats and rabbits

    Pulm Pharmacol

    (1996)
  • P. Holzer

    Acid-sensitive ion channels in gastrointestinal function

    Curr Opin Pharmacol

    (2003)
  • G.R. Dube et al.

    Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels

    Pain

    (2005)
  • A.J. Fox et al.

    Effects of capsazepine against capsaicin- and proton-evoked excitation of single airway C-fibres and vagus nerve from the guinea-pig

    Neuroscience

    (1995)
  • C.J. Dalsgaard et al.

    Evidence for a spinal afferent innervation of the guinea pig lower respiratory tract as studied by the horseradish peroxidase technique

    Neurosci Lett

    (1984)
  • D.R. Springall et al.

    Retrograde tracing shows that CGRP-immunoreactive nerves of rat trachea and lung originate from vagal and dorsal root ganglia

    J Auton Nerv Syst

    (1987)
  • Q.T. Dinh et al.

    Substance P expression in TRPV1 and trkA-positive dorsal root ganglion neurons innervating the mouse lung

    Respir Physiol Neurobiol

    (2004)
  • W. Kummer et al.

    The sensory and sympathetic innervation of guinea-pig lung and trachea as studied by retrograde neuronal tracing and double-labelling immunohistochemistry

    Neuroscience

    (1992)
  • Canning BJ. Encoding of the cough reflex. Pulm Pharmacol Therap 2007, this issue, in press,...
  • R.S. Irwin

    Chronic cough due to gastroesophageal reflux disease: ACCP evidence-based clinical practice guidelines

    Chest

    (2006)
  • A.J. Ing et al.

    Pathogenesis of chronic persistent cough associated with gastroesophageal reflux

    Am J Respir Crit Care Med

    (1994)
  • B.J. Canning et al.

    Reflex mechanisms in gastroesophageal reflux disease and asthma

    Am J Med

    (2003)
  • N. Javorkova et al.

    Acidification of distal esophagus increases cough reflex sensitivity in patients with gastroesophageal reflux disease (GERD) and chronic cough

    Gastroenterology

    (2006)
  • H.R. Berthoud et al.

    Neuroanatomy of extrinsic afferents supplying the gastrointestinal tract

    Neurogastroenterol Motil

    (2004)
  • B.J. Undem et al.

    The role of vagal afferent nerves in chronic obstructive pulmonary disease

    Proc Am Thorac Soc

    (2005)
  • J.N. Sengupta et al.

    Characteristics of vagal esophageal tension-sensitive afferent fibers in the opossum

    J Neurophysiol

    (1989)
  • L.-Y. Lee et al.

    Functional morphology and physiological properties of bronchopulmonary C-fiber afferents

    Anat Rec A Discov Mol Cell Evol Biol

    (2003)
  • J.C. Coleridge et al.

    Afferent vagal C fibre innervation of the lungs and airways and its functional significance

    Rev Physiol Biochem Pharmacol

    (1984)
  • B.J. Undem et al.

    Subtypes of vagal afferent C-fibres in guinea-pig lungs

    J Physiol

    (2004)
  • H.M. Coleridge et al.

    Pulmonary reflexes: neural mechanisms of pulmonary defense

    Ann Rev Physiol

    (1994)
  • M.M. Riccio et al.

    Interganglionic segregation of distinct vagal afferent fibre phenotypes in guinea-pig airways

    J Physiol

    (1996)
  • M. Kollarik et al.

    Mechanisms of acid-induced activation of airway afferent nerve fibres in guinea-pig

    J Physiol

    (2002)
  • B.J. Canning et al.

    Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs

    J Physiol

    (2004)
  • D. Grundy

    Neuroanatomy of visceral nociception: vagal and splanchnic afferents

    Gut

    (2002)
  • M. Falempin et al.

    Vagal mechanoreceptors of the inferior thoracic oesophagus, the lower oesophageal sphincter and the stomach in the sheep

    Pflugers Arch

    (1978)
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      Furthermore, vagal esophageal nociceptors express the capsaicin receptor TRPV1 that modulates responsiveness to noxious stimuli such as acid [10,11]. If this receptor is activated by nociceptive stimuli, the impulse from the receptor is introduced to the solitary nucleus in the medulla oblongata through the superior laryngeal nerve, which is an afferent parasympathetic nerve [10–12]. The esophageal vagal nociceptive afferent nerve subtypes display distinctive responses to acid and these responses are mediated mainly through TRPV1 [13].

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