Polverino et al.

Multidisciplinary Respiratory Medicine 2012, 7:5

http://www.mrmjournal.com/content/7/1/5

REVIEW Open Access

Anatomy and neuro-pathophysiology of the

cough reflex arc
Mario Polverino1*, Francesca Polverino2, Marco Fasolino3, Filippo Andò4, Antonio Alfieri1 and Francesco De Blasio5

Abstract
Coughing is an important defensive reflex that occurs through the stimulation of a complex reflex arc. It accounts
for a significant number of consultations both at the level of general practitioner and of respiratory specialists. In
this review we first analyze the cough reflex under normal conditions; then we analyze the anatomy and the
neuro-pathophysiology of the cough reflex arc. The aim of this review is to provide the anatomic and
pathophysiologic elements of evaluation of the complex and multiple etiologies of cough.
Keywords: Cough, C-Fibers, Rapidly adapting receptors, Reflex arc, Slowly adapting stretch receptors

Review receptor [3-5]. In addition, more airway receptors are in

Cough is one of the most common symptoms for which the external auditory canals, eardrums, paranasal sinuses,
outpatient care is asked [1], accounting for up to 40% of pharynx, diaphragm, pleura, pericardium, and stomach.
the practice activity [2]. Coughing is an important defen- These are probably mechanical receptors only, which can
sive reflex that enhances clearance of secretions and parti- be stimulated by triggers such as touch or displacement.
culates from the airways and protects from aspiration of Impulses from stimulated cough receptors traverse an
foreign materials occurring as a consequence of aspiration afferent pathway via the vagus nerve to a ‘cough center’
or inhalation of particulate matter, pathogens, accumulated in the medulla, which itself may be under some control
secretions, postnasal drip, inflammation, and mediators by higher cortical centers. The cough center generates
associated with inflammation. Under normal conditions an efferent signal that travels down the vagus, phrenic,
cough serves an important protective role in the airways and spinal motor nerves to expiratory musculature to
and lungs, but in some conditions it may become excessive produce the cough.
and nonproductive, and is troublesome and potentially Therefore, the cough reflex arc is constituted by:
harmful to the airway mucosa. These contrasting conse-
quences of coughing can be attributed to the parallel affer- 1. Afferent pathway: Sensory nerve fibers (branches of
ent pathways regulating this important defensive reflex of the vagus nerve) located in the ciliated epithelium of
the airways. the upper airways (pulmonary, auricular, pharyngeal,
Each cough occurs through the stimulation of a complex superior laryngeal, gastric) and cardiac and
reflex arc. This is initiated by the irritation of cough recep- esophageal branches from the diaphragm. The
tors which are found in the trachea, main carina, branch- afferent impulses go to the medulla diffusely.
ing points of large airways, and more distal smaller 2. Central Pathway (cough center): a central
airways; also, they are present in the pharynx. Laryngeal coordinating region for coughing is located in the
and tracheobronchial receptors respond to both mechan- upper brain stem and pons.
ical and chemical stimuli. Chemical receptors sensitive to 3. Efferent pathway: Impulses from the cough center
acid, heat, and capsaicin-like compounds trigger the cough travel via the vagus, phrenic, and spinal motor
reflex via activation of the type 1 vanilloid (capsaicin) nerves to diaphragm, abdominal wall and muscles.
The nucleus retroambigualis, by phrenic and other
spinal motor nerves, sends impulses to the
* Correspondence: [email protected]
1
Lung Diseases Institute, Medical Sciences Department, ASL Salerno, Viale S.
inspiratory and expiratory muscles; and the nucleus
Francesco, Nocera Inferiore (Salerno), Italy
Full list of author information is available at the end of the article

© 2012 Polverino et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Polverino et al. Multidisciplinary Respiratory Medicine 2012, 7:5 Page 2 of 5
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ambiguus, by the laryngeal branches of the vagus to RARs) while preserving C-fiber activity. RARs may act
the larynx. synergistically with other afferent nerve subtypes to in-
duce coughing.
The terminations of the vagal afferents are found in
abundance in the airway mucosa and in the airway wall Slowly adapting stretch receptors (SARs)
from the upper airways to the terminal bronchioles and SARs are highly sensitive to the mechanical forces that
lung parenchyma. Afferent neuronal subtypes can be are put on the lung during breathing. SAR activity
identified based on their physicochemical sensitivity, increases during inspiration and peaks just prior to the
adaptation to sustained lung inflation, neurochemistry, initiation of expiration [13]. SARs are thus thought to be
origin, myelination, conduction velocity (A-fiber, > 3 m/s; the afferent fibers involved in the Hering-Breuer reflex,
C-fiber, < 2 m/s), and sites of termination in the airways. which terminates inspiration and initiates expiration
These attributes can be used to identify at least three when the lungs are adequately inflated. SARs can be dif-
broad classes of airway afferent nerves: ferentiated from RARs in some species based on action
potential conduction velocity, and in most species by
1. Rapidly Adapting Receptors (RAR) their lack of adaptation to sustained lung inflations.
2. Slowly Adapting Stretch Receptors (SARs) SARs may also be differentially distributed throughout
3. C-Fibers the airways: they appear to terminate primarily in the
intrapulmonary airways. SARs also differ from RARs
Rapidly adapting receptors (RAR) with respect to the reflexes they precipitate. SAR activa-
Functional studies of RARs suggest that they terminate tion results in the central inhibition of respiration and
within or beneath the epithelium of both intrapulmonary the inhibition of the cholinergic drive to the airways,
and extrapulmonary airways, but primarily the intrapul- leading to decreased phrenic nerve activity and
monary airways. RARs are differentiated from other air- decreased airway smooth muscle tone (due to a with-
way afferents by their rapid adaptation (in 1 - 2 seconds) drawal of cholinergic nerve activity) [14]. The sensory
to sustained lung inflations [6-19]. Other distinguishing terminals of SARs assume a complex and varying pos-
properties of RARs include their sensitivity to lung col- ition within the airway wall: most of these SARs are
lapse and/or lung deflation, their responsiveness to found in the peripheral airways (associated with alveoli
alterations in dynamic lung compliance (and thus their or bronchioles). Occasionally, SAR dendritic arbors are
sensitivity to bronchospasm), and their conduction vel- associated with the bronchiolar smooth muscle. SARs
ocity (4 to 18 m/s), which is suggestive of myelinated may facilitate coughing by a central cough network via
axons. The sustained activation of RARs produced by dy- activation of brainstem second-order neurons of the
namic lung inflation, bronchospasm, or lung collapse SAR reflex pathway.
indicates that the adaptation of RARs is not attributable
to an electrophysiologic adaptation. Perhaps RARs are C-fibers
thus better defined as dynamic receptors that respond to The majority of afferent nerves innervating the airways
changes in airway mechanical properties (e.g. diameter, and lungs are unmyelinated C-fibers. They are similar in
length, and interstitial pressures). RARs are sporadically many ways to the unmyelinated somatic sensory nerves
active throughout the respiratory cycle, are activated by innervating the skin, skeletal muscle, joints, and bones
the dynamic mechanical forces accompanying lung infla- that respond to noxious chemical and mechanical stimuli
tion and deflation, and become more active as the rate (called nociceptors). In addition to their conduction vel-
and volume of lung inflation increase. RARs are activated ocity (< 2 m/s), airway vagal afferent C-fibers are distin-
by stimuli that evoke bronchospasm or obstruction guished from RARs and SARs by their relative
resulting from mucus secretion or edema. Substances insensitivity to mechanical stimulation and lung infla-
such as histamine, capsaicin, substance P, and bradykinin tion. C-fibers are further distinguished from RARs by the
activate RARs in a way that can be markedly inhibited or observation that they are directly activated by bradykinin
abolished by preventing the local end-organ effects that and capsaicin, not indirectly through effects on smooth
these stimuli produce (e.g. bronchospasm and mucus muscle or the airway vasculature. Moreover, prostaglan-
secretion). RAR activation initiates reflex bronchospasm din E2, adrenaline, and adenosine, which by bronchodi-
and mucus secretion through parasympathetic pathways. lating the airways might inhibit RAR activation by
RARs can also respond to stimuli that evoke cough and bradykinin and capsaicin, actually sensitize C-fibers to
fulfill many criteria for mediating cough. Further evi- capsaicin and bradykinin through direct effects on their
dence for their role in coughing comes from studies of peripheral nerve terminals [15-17]. Morphologic studies
vagal cooling, which blocks cough at temperatures that in rats and in guinea pigs have revealed that afferent C-
selectively abolish activity in myelinated fibers (including fibers innervate the airway epithelium as well as other
Polverino et al. Multidisciplinary Respiratory Medicine 2012, 7:5 Page 3 of 5
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effector structures within the airway wall. C-fibers may complication; however, fractures can occur in patients
synthesize neuropeptides that are subsequently trans- with normal bone density as well [24].
ported to their central and peripheral nerve terminals. A nonproductive cough is a well-recognized complica-
C-fibers are generally quiescent throughout the respira- tion of treatment with angiotensin converting enzyme
tory cycle but are activated by chemical stimuli such as (ACE) inhibitors, occurring in up to 15% of patients trea-
capsaicin, bradykinin, citric acid, hypertonic saline solu- ted with these agents [25]. Although the pathogenesis of
tion, and sulfur dioxide (SO2). Reflex responses evoked the cough is not known with certainty, it has commonly
by C-fiber activation include increased airway parasym- been hypothesized that accumulation of bradykinin,
pathetic nerve activity, and the chemoreflex, character- which is normally degraded in part by ACE, may stimu-
ized by apnea (followed by rapid shallow breathing), late afferent C-fibers in the airway [26].
bradycardia, and hypotension. Stimulants of C-fibers The important observation that cough does not appear
such as capsaicin, bradykinin, SO2, and citric acid evoke to occur with increased frequency in patients treated with
cough in conscious animals and in humans, and capsa- angiotensin II receptor antagonists (which do not increase
icin desensitization abolishes citric acid-induced cough- kinin levels) is consistent with the kinin hypothesis.
ing in guinea pigs. Lesions that compress the upper airway, including ar-
Sex-related differences in cough reflex sensitivity ex- teriovenous malformations and retrotracheal masses,
plain the observation that women are more likely than may present with chronic cough [27-29]. Cough can also
men to develop chronic cough [18-20]. be a symptom of tracheobronchomalacia, which results
The mechanical events of a cough can be divided into from loss of rigid support of the large airways and in-
three phases [21]: spiratory collapse, and is usually seen in conjunction
with obstructive lung disease in patients with a history of
1. Inspiratory phase: Inhalation, which generates the cigarette smoking [30].
volume necessary for an effective cough. Laryngeal sensory neuropathy has been identified as
2. Compression phase: Closure of the larynx combined the cause of chronic cough in 18 of 26 patients with
with contraction of muscles of chest wall, acute onset of cough that was often associated with lar-
diaphragm, and abdominal wall result in a rapid rise yngospasm or throat clearing [31]. Chronic tonsillar en-
in intrathoracic pressure. largement has been proposed as a cause of chronic
3. Expiratory phase: The glottis opens, resulting in high cough, but clinical evidence of this association is limited.
expiratory airflow and the coughing sound. Large One series of 236 patients referred for evaluation in a
airway compression occurs. The high flows dislodge specialized clinic noted tonsillar enlargement in the ab-
mucus from the airways and allow removal from the sence of other known causes of chronic cough in 8
tracheobronchial tree. (3.4%) individuals [32]. Following tonsillectomy, these
patients had decreased cough sensitivity and significantly
The specific pattern of the cough depends on the site improved symptom control. At this moment, these
and type of stimulation. Mechanical laryngeal stimula- observations need further investigations.
tion results in immediate expiratory stimulation (some- Irritation of the external auditory canal by impacted
times termed the expiratory reflex), probably to protect foreign bodies or cerumen is another unusual cause of
the airway from aspiration; stimulation distal to the lar- chronic dry cough [33]. The etiology of the ‘ear-cough’
ynx causes a more prominent inspiratory phase, presum- (or oto-respiratory) reflex is related to stimulation of the
ably to generate the airflow necessary to remove the auricular branch of the vagus nerve (Arnold's nerve)
stimulus. [34,35]. Another rare cause of chronic cough is Holmes-
During vigorous coughing, intrathoracic pressures may Adie syndrome due to autonomic dysfunction affecting
reach 300 mm Hg and expiratory velocities approach the vagus nerve [36] patients present anisocoria, abnor-
800 kilometers per hour [22]. While these pressures and mal deep tendon reflexes, and patchy areas of hyperhi-
velocities are responsible for the beneficial effects of drosis or anhidrosis.
cough on mucus clearance, they are also responsible for In adults, habit (also known as ‘psychogenic’) cough
many of the complications of cough, including exhaus- may rarely be the cause of a chronic cough that remains
tion, self-consciousness, insomnia, headache, dizziness, troublesome despite a thorough evaluation, including
musculoskeletal pain, hoarseness, excessive perspiration, ruling out tic disorders.
urinary incontinence [23]. Cough-induced rib fractures Differences among several sites from which cough
are another painful and potentially serious complication stimuli can originate may result in variations in the
of chronic cough. Fractures often involve multiple ribs, sounds and patterns of coughing.
particularly ribs five through seven. Women with Laryngeal stimulation produces a choking type of
decreased bone density are at the greatest risk of this cough without a preceding inspiration.
Polverino et al. Multidisciplinary Respiratory Medicine 2012, 7:5 Page 4 of 5
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Inadequate mucociliary clearance mechanisms (as in Received: 17 May 2012 Accepted: 18 June 2012
bronchiectasis or cystic fibrosis) may produce a pattern Published: 18 June 2012

of coughing with less violent acceleration of air and a se-

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doi:10.1186/2049-6958-7-5
Cite this article as: Polverino et al.: Anatomy and neuro-pathophysiology
of the cough reflex arc. Multidisciplinary Respiratory Medicine 2012 7:5.

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