Vagal afferent nerves regulating the cough reflex☆
Introduction
Coughing can be evoked in animals and in human subjects by inhalation of particulates, acids, irritant gases (e.g. sulfur dioxide), cigarette smoke, nicotine, capsaicin, bradykinin, prostanoids, hypo- and hypertonic solutions, and by mechanical probing of the tracheal, laryngeal and large bronchial mucosa (Widdicombe, 1954a, Gravenstein et al., 1954, Karlsson et al., 1988, Choudry et al., 1989, Hansson et al., 1994, Lalloo et al., 1995, Nishino et al., 1996, Karlsson and Fuller, 1999). Coughing is not so readily initiated by bronchospasm or by static changes in airway pressure (Chausow and Banner, 1983, Butler et al., 1995, House et al., 2004, Canning et al., 2004, El-Hashim and Amine, 2005). Regardless of the stimulus, coughing is attenuated by anesthesia (May and Widdicombe, 1954, Nishino et al., 1996, Tagaito et al., 1998, Canning et al., 2004) and completely abolished by vagotomy and/or vagal cooling (Widdicombe, 1954a, Klassen et al., 1951, Adams et al., 1987, Tatar et al., 1988, Canning et al., 2004). These and other observations indicate that the cough reflex is initiated by activation of chemically and mechanically sensitive vagal afferent nerves (Widdicombe, 1998). Afferent nerves innervating other viscera as well as somatosensory nerves innervating the chest wall, diaphragm and abdominal musculature play a less essential but important accessory role in regulating cough (Kondo et al., 1998, Morice et al., 2004). The mechanisms by which tussive stimuli activate the various afferent nerves regulating cough is reviewed in detail elsewhere in this issue (Kollarik and Undem, 2006). This review will describe the vagal afferent nerve subtypes innervating the airways and their proposed roles in regulating cough.
Section snippets
Classification of airway afferent nerve subtypes
Airway afferent nerves are differentiated based on their physical and chemical sensitivity, adaptation to mechanical stimulation, neurochemistry, origin, myelination, conduction velocity, activity during tidal breathing, reflexes associated with their activation, and sites of termination in the airways, lungs and brain stem (Table 1; Fig. 1). The utility of the various approaches used to define subtypes of airway afferent nerves is limited largely by the lack of specificity of the
Rapidly adapting receptors
RARs terminate in the intrapulmonary airways of all species studied and in the extrapulmonary airways of dogs and cats. Anatomically, the structure of RAR terminations in the airway wall is poorly described (Widdicombe, 2001, Widdicombe, 2003). Physiologically, RAR terminals are dynamic receptors that respond to changes in airway mechanics (e.g. diameter, length, interstitial and intraluminal pressures). They are functionally differentiated from other airway afferent nerves by their rapid (1–2
Peripheral interactions
In guinea pigs and rats, activation of airway C-fibers evokes axon reflex-dependent peripheral release of the neuropeptides substance P, NKA and CGRP (Barnes, 2001). Axon reflexes in the airways and lungs induce bronchospasm, vasodilatation, edema, leukocyte recruitment, mucus secretion, altered parasympathetic nerve activity and stimulation of endothelial and epithelial cells (Lundberg et al., 1983, Kuo et al., 1990, Manzini, 1992, Piedimonte et al., 1993, Baluk et al., 1995, Ricciardolo et
Concluding remarks
It is well established that vagal afferent nerves regulate coughing. It remains somewhat unclear, however, what relative role the identified afferent nerve subtypes play in mediating cough. Species differences may account for some of this uncertainty, but it is also possible that multiple pathways for cough exist. Regarding the specific subtypes of afferents identified in the airways and lungs and their role in cough, intrapulmonary RARs and C-fibers, and SARs throughout the airways and lungs
References (157)
- et al.
Respiratory reflexes in the anesthetized miniature swine
Resp. Physiol.
(1987) - et al.
A comparative study of irritant and type J receptors in the cat
Resp. Physiol.
(1974) Neurogenic inflammation in the airways
Resp. Physiol.
(2001)Sensory receptor activation by mediators of defense reflexes in guinea-pig lungs
Resp. Physiol.
(1997)- et al.
Characterization of intrapulmonary, rapidly adapting receptors of guinea pigs
Resp. Physiol.
(1982) - et al.
Ruthenium red decreases capsaicin and citric acid-induced cough in guinea pigs
Neurosci. Lett.
(1991) - et al.
Pharmacological studies of allergic cough in the guinea pig
Eur. J. Pharmacol.
(1995) Interactions between vagal afferent nerve subtypes mediating cough
Pulm. Pharmacol. Ther.
(2002)- et al.
Antitussive activity of the tachykinin NK1 receptor antagonist, CP-99994, in dogs
Eur. J. Pharmacol.
(2004) - et al.
Effect of 5-hydroxytryptamine on vagal C-fiber subtypes in guinea pig lungs
Pulm. Pharmacol. Ther.
(2005)
Role of vagal afferents in the reflex effects of capsaicin and lobeline in monkeys
Resp. Physiol.
Stretch receptor-associated expression of alpha 3 isoform of the Na+, K+-ATPase in rat peripheral nervous system
Neuroscience
The role of substance P and bradykinin in the cough reflex and bronchoconstriction in guinea-pigs
Eur. J. Pharmacol.
Sensitivity of vagal afferent endings to chemical irritants in the rat lung
Resp. Physiol.
Cough reflex in allergic dogs
Eur. J. Pharmacol.
Voluntary suppression of cough induced by inhalation of capsaicin in healthy volunteers
Resp. Med.
Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines
Chest
Central nervous pathways and control of the airways
Resp. Physiol.
The role of capsaicin-sensitive C-fibre afferent nerves in the cough reflex
Pulm. Pharmacol.
Pharmacological regulation of the cough reflex — from experimental models to antitussive effects in man
Pulm. Pharmacol. Ther.
Regional sensitivity of the respiratory tract to stimuli causing cough and reflex bronchoconstriction
Resp. Med.
The sensory and sympathetic innervation of guinea-pig lung and trachea as studied by retrograde neuronal tracing and double-labelling immunohistochemistry
Neuroscience
A comparative study of the effects of citric acid, capsaicin and resiniferatoxin on the cough challenge in guinea-pig and man
Pulm. Pharmacol.
Afferent properties and reflex functions of bronchopulmonary C-fibers
Resp. Physiol.
Antitussive properties of inhaled bronchodilators on induced cough
Chest
Responses of bronchial C-fiber afferents of the rabbit to changes in lung compliance
Resp. Physiol. Neurobiol.
The activities of lung stretch and irritant receptors during cough
Neurosci. Lett.
Potassium channel blockade induces action potential generation in guinea-pig airway vagal afferent neurones
J. Auton. Nerv. Syst.
Role of tachykinins in cough
Sulfur dioxide-induced bronchoconstriction via ruthenium red-sensitive activation of sensory nerves
Respiration
NK1 receptors mediate leukocyte adhesion in neurogenic inflammation in the rat trachea
Am. J. Physiol.
Substance P-immunoreactive sensory axons in the rat respiratory tract: a quantitative study of their distribution and role in neurogenic inflammation
J. Comp. Neurol.
Comparative effects of inhaled leukotriene C4, leukotriene D4, and histamine in normal human subjects
Thorax
Enhanced lung C-fiber responsiveness in sensitized adult guinea pigs exposed to chronic tobacco smoke
J. Appl. Physiol.
Identification of vagal sensory receptors in the rat lung: are there subtypes of slowly adapting receptors?
J. Physiol.
Central antitussive activity of the NK1 and NK2 tachykinin receptor antagonists, CP-99, 994 and SR, 48968, in the guinea-pig and cat
Br. J. Pharmacol.
Substance P contributes to rapidly adapting receptor responses to pulmonary venous congestion in rabbits
J. Physiol.
Neurochemical characterisation of sensory receptors in airway smooth muscle: comparison with pulmonary neuroepithelial bodies
Histochem. Cell Biol.
Role of airway receptors in the reflex responses of human inspiratory muscles to airway occlusion
J. Physiol.
Endogenous neurokinins facilitate synaptic neurotransmission in guinea pig airway parasympathetic ganglia
Am. J. Physiol.-Regul. Integr. Comp. Physiol.
Multiple mechanisms of reflex bronchospasm in guinea pigs
J. Appl. Physiol.
Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs
J. Physiol.
Mechanism of baroreceptor adaptation in dogs: attenuation of adaptation by the K+ channel blocker 4-aminopyridine
J. Physiol.
Comparison of the tussive effects of histamine and methacholine in humans
J. Appl. Physiol.
Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin, and histamine
Am. Rev. Resp. Dis.
Afferent vagal C fibre innervation of the lungs and airways and its functional significance
Rev. Physiol. Biochem. Pharmacol.
Reflex tracheal gland secretion evoked by stimulation of bronchial C-fibers in dogs
J. Appl. Physiol.
Origin and colocalization of CGRP- and SP-reactive nerves in cat airway epithelium
J. Appl. Physiol.
Cited by (196)
Chemical Space of Small Molecule Exploration for the Elucidation of Cough Suppressant Pharmacology of Ying Su Ke/Zi
2024, Journal of Herbal MedicineChronic Cough and Obstructive Sleep Apnea
2024, Sleep Medicine ClinicsDifferential inhibition of cough by GABA<inf>A</inf> and GABA<inf>B</inf> receptor antagonists in the nucleus of the solitary tract in cats
2023, Respiratory Physiology and NeurobiologyTreatment of chronic cough: P2X3 receptor antagonists and beyond
2022, Pharmacology and TherapeuticsModeling and simulation of vagal afferent input of the cough reflex
2022, Respiratory Physiology and Neurobiology
- ☆
This paper is part of a special issue entitled “Cough and its Regulation”, guest-edited by John G. Widdicombe and Bradley J. Undem.