Vagal afferent nerves regulating the cough reflex

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Abstract

Coughing is initiated by activation of mechanically and chemically sensitive vagal afferent nerves innervating the airways. All afferent nerve subtypes innervating the airways can modulate the cough reflex. Rapidly adapting and slowly adapting stretch receptors (RARs and SARs, respectively) innervating the intrapulmonary airways and lung may enhance and facilitate coughing. Activation of intrapulmonary C-fibers has been shown to inhibit coughing in anesthetized animals. Extrapulmonary C-fibers and RARs can initiate coughing upon activation. C-fiber-dependent coughing is uniquely sensitive to anesthesia. Tracheal and bronchial C-fibers may also interact with other afferents to enhance coughing. Recent studies in anesthetized guinea pigs have identified a myelinated afferent nerve subtype that can be differentiated from intrapulmonary RARs and SARs and play an essential role in initiating cough. Whether these “cough receptors” are the guinea pig equivalent of the irritant receptors described in the extrapulmonary airways of other species is unclear.

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

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    This paper is part of a special issue entitled “Cough and its Regulation”, guest-edited by John G. Widdicombe and Bradley J. Undem.

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