Chest
Volume 129, Issue 1, Supplement, January 2006, Pages 33S-47S
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Supplement
Diagnosis and Management of Cough: ACCP Evidence-Based Clinical Practice Guidelines
Anatomy and Neurophysiology of the Cough Reflex: ACCP Evidence-Based Clinical Practice Guidelines

https://doi.org/10.1378/chest.129.1_suppl.33SGet rights and content

Objectives:

To describe the anatomy and neurophysiology of the cough reflex.

Methods:

A review of the literature was carried out using PubMed and the ISI Web of Knowledge from 1951 to 2004. Most of the referenced studies were carried out in animals

Conclusions:

Studies carried out in animals provide suggestive but inconclusive evidence that C-fibers and rapidly adapting receptors (RARs) arising from the vagus nerves mediate coughing. Recent studies also have suggested that a vagal afferent nerve subtype that is not readily classified as a RAR or a C-fiber may play an important role in regulating cough. Afferent nerves innervating other viscera, as well as somatosensory nerves innervating the chest wall, diaphragm, and abdominal musculature also likely play a less essential but important accessory role in regulating cough. The responsiveness and morphology of the airway vagal afferent nerve subtypes and the extrapulmonary afferent nerves that regulate coughing are described.

Section snippets

Rapidly Adapting Receptors

The anatomy of rapidly adapting receptor (RAR) terminations in the airway wall is unknown. Functional studies11, 12, 13, 14, 15, 16, 17 of RARs suggest that they terminate within or beneath the epithelium of both intrapulmonary and extrapulmonary airways, but primarily the intrapulmonary airways. RARs are differentiated from other airway afferents by their rapid adaptation (ie, 1 to 2 s) to sustained lung inflations (Fig 2).13, 14, 15, 16, 17, 18, 19 Other distinguishing properties of RARs

Peripheral Interactions

Activated C-fibers can release the neuropeptides substance P, neurokinin A, and calcitonin gene-related peptide from their peripheral nerve terminals without involvement of the CNS, and even without action potential formation.59 This process is called the axon reflex, and has been well-described in human skin and in the viscera of many species. Axon reflexes in the airways and lungs of guinea pigs result in bronchospasm, mucus secretion, vasodilatation, edema, leukocyte recruitment, altered

Cough Evoked From the Ear (Arnold Reflex)

Afferent nerves carried by the auricular branch of the vagus nerve (ie, the Arnold nerve) innervate the external auditory meatus.114 In a small subset of patients (< 5%), several visceral reflexes, including cough, may be evoked by the mechanical stimulation of the ear. Tracing studies115 in cats have shown that afferent neurons carried by the Arnold nerve have their cell bodies in the superior vagal (jugular) ganglia, and terminate in several areas throughout the brainstem, including the

CONCLUDING REMARKS

Studies carried out in animals have provided clear evidence that vagal afferent nerves regulate coughing. It remains unclear, however, what relative role the identified afferent nerve subtypes play in mediating cough. Evidence both for and against the role of C-fibers and RARs has been reported. These conflicting data suggest that the activation of both afferent nerve subtypes may be required to induce coughing, or that a previously unrecognized airway afferent nerve subtype subserves a primary

REFERENCES (140)

  • DR Bergren

    Sensory receptor activation by mediators of defense reflexes in guinea-pig lungs

    Respir Physiol

    (1997)
  • T Morikawa et al.

    Actions of moguisteine on cough and pulmonary rapidly adapting receptor activity in the guinea pig

    Pharmacol Res

    (1997)
  • BJ Canning

    Interactions between vagal afferent nerve subtypes mediating cough

    Pulm Pharmacol Ther

    (2002)
  • ES Schelegle et al.

    An overview of the anatomy and physiology of slowly adapting pulmonary stretch receptors

    Respir Physiol

    (2001)
  • FB Sant'Ambrogio et al.

    Contraction of trachealis muscle and activity of tracheal stretch receptors

    Respir Physiol

    (1988)
  • AL Wang et al.

    Vagal bronchopulmonary C-fibers and acute ventilatory response to inhaled irritants

    Respir Physiol

    (1996)
  • LY Lee et al.

    Afferent properties and reflex functions of bronchopulmonary C-fibers

    Respir Physiol

    (2001)
  • PJ Barnes

    Neurogenic inflammation in the airways

    Respir Physiol

    (2001)
  • T Nishino et al.

    Cough and other reflexes on irritation of airway mucosa in man

    Pulm Pharmacol

    (1996)
  • HA Hutchings et al.

    Voluntary suppression of cough induced by inhalation of capsaicin in healthy volunteers

    Respir Med

    (1993)
  • MA McAlexander et al.

    Potassium channel blockade induces action potential generation in guinea-pig airway vagal afferent neurones

    J Auton Nerv Syst

    (2000)
  • M Dobretsov et al.

    Stretch receptor-associated expression of alpha 3 isoform of the Na+, K+-ATPase in rat peripheral nervous system

    Neuroscience

    (2003)
  • DC Bolser et al.

    Pharmacological studies of allergic cough in the guinea pig

    Eur J Pharmacol

    (1995)
  • R Yasumitsu et al.

    Effects of specific tachykinin receptor antagonists on citric acid-induced cough and bronchoconstriction in unanesthetized guinea pigs

    Eur J Pharmacol

    (1996)
  • DF Rogers et al.

    Opioid inhibition of neurally mediated mucus secretion in human bronchi

    Lancet

    (1989)
  • PJ Fleming et al.

    Functional immaturity of pulmonary irritant receptors and apnea in newborn preterm infants

    Pediatrics

    (1978)
  • CM Schramm

    Current concepts of respiratory complications of neuromuscular disease in children

    Curr Opin Pediatr

    (2000)
  • P Mosconi et al.

    Epidemiology and risk factors of pneumonia in critically ill patients: Intensive Care Unit Group for Infection Control

    Eur J Epidemiol

    (1991)
  • R Shannon et al.

    Ventrolateral medullary respiratory network and a model of cough motor pattern generation

    J Appl Physiol

    (1998)
  • G Sant'Ambrogio et al.

    Airway receptors in cough

    Bull Eur Physiopathol Respir

    (1984)
  • MM Ricco et al.

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

    J Physiol

    (1996)
  • J Widdicombe

    Functional morphology and physiology of pulmonary rapidly adapting receptors (RARs)

    Anat Rec

    (2003)
  • JC Coleridge et al.

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

    Rev Physiol Biochem Pharmacol

    (1984)
  • A Jonzon et al.

    Rapidly adapting receptor activity in dogs is inversely related to lung compliance

    J Appl Physiol

    (1986)
  • MA McAlexander et al.

    Adaptation of guinea-pig vagal airway afferent neurones to mechanical stimulation

    J Physiol

    (1999)
  • AI Pack et al.

    Response of pulmonary rapidly adapting receptors during lung inflation

    J Appl Physiol

    (1983)
  • SP Mohammed et al.

    Effects of aerosol-applied capsaicin, histamine and prostaglandin E2 on airway sensory receptors of anaesthetized cats

    J Physiol

    (1993)
  • BJ Canning et al.

    Multiple mechanisms of reflex bronchospasm in guinea pigs

    J Appl Physiol

    (2001)
  • JP Joad et al.

    Nitric oxide contributes to substance P-induced increases in lung rapidly adapting receptor activity in guinea-pigs

    J Physiol

    (1997)
  • AC Bonham et al.

    Substance P contributes to rapidly adapting receptor responses to pulmonary venous congestion in rabbits

    J Physiol

    (1996)
  • BJ Canning et al.

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

    J Physiol

    (2004)
  • M Tatar et al.

    Lung C-fibre receptor activation and defensive reflexes in anaesthetized cats

    J Physiol

    (1988)
  • M Tatar et al.

    Laryngeal and tracheobronchial cough in anesthetized dogs

    J Appl Physiol

    (1994)
  • NC Barnes et al.

    Comparative effects of inhaled leukotriene C4, leukotriene D4, and histamine in normal human subjects

    Thorax

    (1984)
  • G Joos et al.

    Effect of inhaled substance P and neurokinin A on the airways of normal and asthmatic subjects

    Thorax

    (1987)
  • M Fujimura et al.

    Effects of methacholine induced bronchoconstriction and procaterol induced bronchodilation on cough receptor sensitivity to inhaled capsaicin and tartaric acid

    Thorax

    (1992)
  • K Shinagawa et al.

    Participation of thromboxane A(2) in the cough response in guinea-pigs: antitussive effect of ozagrel

    Br J Pharmacol

    (2000)
  • CA Richardson et al.

    Modulation of pulmonary stretch receptors and airway resistance by parasympathetic efferents

    J Appl Physiol

    (1984)
  • J Yu et al.

    Structure of slowly adapting pulmonary stretch receptors in the lung periphery

    J Appl Physiol

    (2003)
  • T Sudo et al.

    Responses of tracheobronchial receptors to inhaled furosemide in anesthetized rats

    Am J Respir Crit Care Med

    (2000)
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