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

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THE ANATOMICAL RECORD PART A 270A:2–10 (2003)
Functional Morphology and
Physiology of Pulmonary Rapidly
Adapting Receptors (RARs)
JOHN WIDDICOMBE*
Guy’s, King’s and St. Thomas’ School of Biomedical Sciences, Human Physiology and
Aerospace Medicine, London, UK
ABSTRACT
Rapidly adapting receptors (RARs) in the airway mucosa are found
from the nasopharynx to the bronchi. They have thin (A␦) vagal afferent
fibres and lie in and under the epithelium, but their morphology has not
been defined. They are very sensitive to mechanical stimuli, and have a
rapidly adapting irregular discharge. However, with in vitro preparations
they are rather insensitive to chemical stimuli, apart from acid and nonisosmolar solutions. Their pattern of response varies with site. RARs in the
nasopharynx, larynx, and trachea usually respond only during the onset of
stimuli, while those in the trachea often have an off-response as well. Those
in the bronchi are less rapidly adapting and more chemosensitive. Their
membranes have mechanosensitive and acid-sensitive ion channels, but no
vanilloid receptors. In vivo RARs are sensitive to a wide range of chemical
irritants and mediators, and presumably are excited secondarily to mechanical changes in the mucosa and airway smooth muscle. In the central
nervous system (CNS) they interact with other vagal afferent pathways.
The reflexes they cause vary with site (inspiratory efforts from the nasopharynx, cough or expiratory efforts from the larynx and trachea, and deep
breaths or tachypnoea from the bronchi). Pathways from RARs and other
vagal reflexes show plasticity at the peripheral, ganglionic, and CNS levels.
Anat Rec Part A 270A:2–10, 2003. © 2003 Wiley-Liss, Inc.
Key words: rapidly adapting receptors; cough; augmented
breaths; hyperpnoea; bronchoconstriction
Lung rapidly adapting receptors (RARs) were first identified by Keller and Loeser (1929) (Fig. 1). Using multifibre records from the vagus nerves of rabbits, they showed
that some receptors responded with a rapidly adapting
discharge to lung inflation and deflation, and to mechanical stimulation. They concluded that these receptors were
responsible for cough. Adrian (1933), in his classic singlefibre analysis of lung receptors, studied mainly slowly
adapting receptors (SARs). He also described RARs that
responded mainly to deflation, but did not discuss their
reflex actions. Knowlton and Larrabee (1946) were the
first to quantitate “adaptation rate,” defining it as the
percentage decrease in impulse frequency from a receptor
after 1 sec of maintained stimulus. They showed a clear
distinction between SARs and RARs (Fig. 2), and concluded that the latter caused augmented breaths (sighs)
and possibly the deep breaths that precede the expiratory
effort of coughing.
©
2003 WILEY-LISS, INC.
Widdicombe (1954a) extended these studies. He showed
that lung receptors had a wide range of adaptation rates,
from those that discharged only during a change in stimulus (100% adaptation; usually found in the trachea) to
those with slower adaptation (usually found in the bronchi). The former, but not the latter, had a conspicuous
off-stimulus response, like Pacinian corpuscles (Fig. 3);
they had an irregular firing pattern, and were also rather
insensitive to chemical irritant stimuli (see below). He
*Correspondence to: John Widdicombe, 116 Pepys Road, London SW20 8NY, UK. Fax: ⫹44-(0)-208-286-1815.
E-mail: JohnWiddicombeJ@aol.com
Received 23 May 2002; Accepted 5 September 2002
DOI 10.1002/ar.a.10003
RAPIDLY ADAPTING RECEPTORS (RARS)
3
Fig. 1. Oscillograph record of action potentials in the vagus nerve of a rabbit. Uppermost trace,
ventilation; middle trace, action potentials; lowest trace, ECG. After the arrow the receptor(s) were stimulated
by repeated insertion of a fine catheter into the trachea, giving rapidly adapting discharges. From Keller and
Loeser (1929).
Fig. 2. Responses to inflation of the lungs of two kinds of afferent
fibre in the vagus of a cat. (A) The first receptor adapts slowly, and (B) the
second adapts very rapidly to maintained inflation of the lungs. Upper
traces, intratracheal pressure; lower traces, action potentials; time in 0.1
sec. From Knowlton and Larrabee (1946).
concluded that the former caused coughing and the latter
augmented breathing. Both could be differentiated from
SARs, which had a regular firing pattern and a slower
adaptation rate, often lay deeper in the lungs, and were
responsible for the Breuer-Hering inflation reflex (inhibition of inspiration and prolongation of expiration).
DEFINITION OF RARS
RARs should be defined by their adaptation rate to a
maintained stimulus. While this appears to be a simple
test, in practice two problems arise. First, if an increase in
lung or airway volume is the chosen stimulus, what
should be defined as the “true” stimulus? If the volume
Fig. 3. Action potentials in a single afferent fibre from an RAR in the
isolated trachea of an anaesthetised cat. Upper record, tracheal pressure; lower record, action potentials. A: Inflation of the trachea with
discharges at onset and removal of the stimulus. B: Deflation of the
trachea with similar responses. C: Stimulation of the receptor by touch
with an endotracheal catheter. From Widdicombe (1954a).
change is constant, transpulmonary pressure during the
volume change will decrease because of stress relaxation.
If the pressure is kept constant, the volume will be increase for the same reason. Usually volume is kept constant, on the assumption that this is the “true” stimulus
for the RAR. Second, RARs show a wide range of adaptation rates, which overlap with those for SARs (Widdicombe, 1954a). The dividing point is arbitrary. This is not
a problem for RARs, with their near 100% adaptation
rates, or for SARs, with their near-zero adaptation rates.
But receptors in the middle of the range may be difficult to
define.
Fibre diameter and conduction velocity are also poor
indices. RARs have fibres that are myelinated and are
mainly in the A␦ range, whereas SARs have myelinated
fibres mainly in the A␤ and A␥ ranges. But again, there is
considerable overlap.
4
WIDDICOMBE
Fig. 4. A diagram of the afferent pathways involved in cough, with
their stimuli and probable mechanisms of action. The right side of the
figure shows the epithelium with three types of sensory receptors (RARs,
A␦-fibre nociceptors, and C-fibre nociceptors) in and under the epithelium, a few of the stimuli that excite them (in boxes), and their afferent
fibre types that run in the vagus nerves. The nodose ganglion contains
the cell bodies of the RARs, and the jugular ganglion contains the cell
bodies of the two nociceptive receptors. The enclosed table shows
membrane ion channels that may be activated by various stimuli for the
three types of receptor. From Undem et al. (2002).
A distinction may be derived from the fact that RARs
are located mainly in and under the epithelium, whereas
SARs lie in the airway smooth muscle (Sant’Ambrogio et
al., 1978); however, this test in usually difficult to apply
experimentally. It is not difficult to distinguish RARs from
C-fibre receptors, by conduction velocity measurements,
although both respond to many of the same stimuli.
Undem and colleagues (Riccio et al., 1996a; Kajekar et
al., 1999; Undem and Carr, 2001; Carr and Ellis, 2002;
Undem et al., 2002) recently described a group of nociceptive A␦ fibres with sensory nerve terminals in the epithelium and cell bodies in the vagal jugular ganglia (the cell
bodies of RARs are mainly in the nodose ganglia). Although they are not called RARs, they resemble them in
their fibre conduction velocities, in that they fire irregularly, and their discharge to a maintained mechanical
stimulus adapts rather rapidly (apparently, adaptation
indices were not measured in these studies). These fibres
are discussed briefly below.
is unclear; the nose is not distensible, so adaptation rates
cannot easily be determined. In the tracheobronchial tree
they are concentrated at the carina and hilar regions
(Widdicombe, 1954a; 1986, 1996a, 2001). In the dog they
are distributed around the whole circumference, unlike
SARs, which are mainly in the posterior walls (Mortola et
al., 1975; Sant’Ambrogio et al., 1978).
Morphology has not been determined for RARs at any
airway site. Although putative sensory nerves have been
identified, the distribution of their terminals has not been
mapped out, and it is usually impossible to determine
whether they are parts of RARs or of nociceptive C- or
A␦-fibre receptors (Widdicombe, 2001). Early claims that
the intraepithelial nonmyelinated nerves were components of RARs were based on the following: 1) both histological and physiological (nerve impulse recording) studies
showed a concentration of nerves at the carina, and a
paucity in the smaller bronchi; 2) at least some nonmyelinated epithelial nerves connect to subepithelial myelinated fibres (Widdicombe, 1964); and 3) mice and ferrets,
which lack a cough reflex, do not have intraepithelial
nerves (Widdicombe, 1986, 2001; Karlsson et al., 1988).
Teleologically, an epithelial site seemed consistent with
the great sensitivity of RARs to intraluminal mechanical
stimuli. Degeneration studies have established that the
LOCATION AND MORPHOLOGY OF RARS
As assessed by adaptation rate and conduction velocity,
RARs are found in the airway wall from the nasopharynx
to the larger bronchi (Sant’Ambrogio and Widdicombe,
2001; Widdicombe, 2001). Whether they exist in the nose
RAPIDLY ADAPTING RECEPTORS (RARS)
Fig. 5. Histological appearance of an epithelial receptor in the bronchial wall of a child. Note the nerve filaments between the columnar cells
of the epithelium. n.ter., nerve termination; epith., epithelium; br.gl.,
bronchial gland; ca.pl., cartilaginous plate. ⫻275. From Larsell and Dow
(1933).
intraepithelial nerves are sensory and not motor (Das et
al., 1979; Baluk et al., 1992). Destruction of the epithelium
does not remove the mechanical sensitivity of RARs (Mortola et al., 1975; Undem et al., 2002). However, a recent
study in the guinea pig has shown, by retrograde nerve
staining, that RARs lie under the epithelium, whereas at
least some of their terminals of nociceptive C- and A␦nerves (see below) lie inside the epithelium (Hunter and
Undem, 1999; Undem et al., 2002) (Fig. 4). This is consistent with a number of histological studies showing that at
least some intraepithelial nerve complexes join to myelinated fibres in the submucosa (Larsell and Dow, 1933;
Widdicombe, 1964, 2002) (Fig. 5); this holds true from the
larynx to the bronchi (Undem and Weinreich, 1993; Tsuda
et al., 1998).
The surface extent of tracheal RARs in the guinea pig is
small (0.5–1 mm in diameter), according to previous studies in which the surface was probed while receptor discharge was recorded (Undem and Weinreich, 1993; Fox,
1996). Physiological studies in dogs have shown that tracheal RARs have branches deeper in the submucosa (Mortola et al., 1975; Undem et al., 2002). Kappagoda et al.
(1990) mapped out a putative RAR (Ravi and Kappagoda,
1990) (Fig. 6). This shows myelinated fibres, close to mucosal venules, which lose their myelin sheaths and end as
encapsulated bodies. They send fibres under but not into
the epithelium, in agreement with the findings of Undem
et al. (2002). They may contain the neuropeptides substance P and calcitonin gene-related peptide, as do the
nerves in the epithelium, although this view is disputed
for RARs (Undem et al., 2002); the neuropeptide-containing terminals may be part of the nociceptive A␦-fibre receptors.
The fibres from SARs, RARs, and C-fibre receptors all
travel in the vagus nerves, while those from neuroepithelial bodies (NEBs) run in the vagi and spinal nerves, as
shown by retrograde staining (Adriaensen et al., 1998)
5
Fig. 6. Hypothetical location and structure of an RAR. It is proposed
that the receptor is localised in the extracellular space in close proximity
to bronchial venules. An increase in hydrostatic pressure in bronchial
venules or vasoactive substances, such as histamine and substance P,
will increase extravascular fluid volume and stimulate the receptors.
Irritant gases in the airways will also stimulate the ending. VA, vagal
afferent fibre; BrV, bronchial venule; L, lymphatic; g, gaps between
endothelial cells, r, pharmacological receptors; SM, smooth muscle; E,
epithelial cells. From Ravi and Kappagoda (1990).
(see “Functional Morphology of Pulmonary Neuroepithelial Bodies: Extremely Complex Airway Receptors,” Adriaensen et al., 2003, this volume). Most of the RAR cell
bodies are in the nodose ganglia, whereas the cell bodies of
nociceptive C-and A␦-fibres are mainly in the jugular ganglia (Riccio et al., 1996a; Undem et al., 2002). This distinction has important implications for the interaction of afferent pathways at the ganglionic level (see below).
PHYSIOLOGY OF RARS
As indicated above, RARs have a wide range of properties. Those in the nasopharynx, and many in the trachea
discharge only during the application and removal of a
mechanical stimulus, i.e., they have a 100% adaptation
index (Widdicombe, 1954a, 2001; Sant’Ambrogio and Widdicombe, 2001). They are usually silent in eupnoea and
are extremely sensitive to mechanical stimuli, but are not
very sensitive to the direct application of chemical agents,
unlike the nociceptive C- and A␦-fibre receptors. RARs in
the trachea are sensitive to acid and to nonisosmolar
solutions (Pisarri et al., 1992; Undem and Weinreich,
1993; Undem and Riccio, 1997, Undem and Carr, 2001;
Undem et al., 2002). They are stimulated by inflation and
deflation of the airway, and some are active, with a respiratory phase in eupnoea. RARs in the larynx, often called
“irritant receptors,” have a very rapidly adapting response
to mechanical stimuli, but are also sensitive to chemical
irritant stimuli such as distilled water, cigarette smoke,
CO2, and volatile anaesthetics (Mathew and Sant’Ambrogio,
1988; Sant’Ambrogio et al., 1995; Sant’Ambrogio and Widdicombe, 2001). They are stimulated by hypo- and hyperosmolar solutions—in the former case, especially if there
is a deficiency of chloride.
The mechanisms of RAR excitation have been studied
mainly in the in vitro trachea, usually of the guinea pig
6
WIDDICOMBE
(Fox, 1996; Carr and Undem, 2001a). The membrane
channels for mechanical stimulation, the most powerful
means of exciting RARs, have not been identified, but are
presumably mechanically-gated channels, as in other
mechanoceptors. Although the RARs adapt rapidly, they
do not become insensitive to repeated stimuli (McAlexander et al., 1999; Undem et al., 2002), and thus differ
from rapidly adapting receptors in somatic tissues. Their
membranes contain channels of the acid-sensing ion channel family (Undem et al., 2002), which explains their response to acid solutions. Unlike nociceptive C- and A␦receptors, the RARs in the guinea pig do not have
excitatory sodium channels or vanilloid receptors (VR1
channels). However, in the cat and rabbit, RARs are stimulated by ammonia and veratridine (Matsumoto et al.,
1994). How these agents work is not clear, although it is
thought to be by opening sodium channels; the fibres may
be from nociceptive A␦-receptors. Again, unlike the nociceptive endings, RARs do not contain tachykinins (Undem
et al., 2002), although one study (Kappagoda et al., 1990)
proposed that tachykinins are present in RAR terminals
in the subepithelium. They are inhibited by dopamine,
acting on D2 receptors (Jackson and Simpson, 2000),
which could be of therapeutic significance in the treatment of cough.
Extensive in vitro studies with guinea pig trachea have
shown that the RARs are relatively insensitive to many
chemicals that can excite the nociceptive C- and A␦-receptors. These agents include capsaicin, histamine, bradykinin, prostaglandins, 5-hydroxytryptamine, and platelet
activating factor (Fox et al., 1993; Fox, 1996; Undem and
Carr, 2001; Undem et al., 2002). These substances have
been shown to induce coughing when given by aerosol to
subjects of many different species (including humans) in
vivo. These observations have been used to support the
claim that in addition to the RARs, the C-fibre receptors
can cause coughing (Fox, 1996; Karlsson and Fuller,
1999). However, all of these substances excite the RARs in
vivo (Sellick and Widdicombe, 1971; Bergren et al., 1984;
Bergren and Myers, 1984; Yu and Roberts, 1990; Hargreaves et al., 1993; Mohammed et al., 1993; Bergren,
1997; Widdicombe 1996a, 1998, 2001; Undem and Carr,
2001). The different RAR responses in vitro and in vivo
can be explained by the exquisite mechanosensitivity of
the RARs, and the fact that they respond secondarily to
changes in the properties of the mucosa. Thus they are
stimulated by airway smooth muscle contraction
(Coleridge and Coleridge, 1986; Coleridge et al., 1989;
Canning, 2002), by mucosal vasodilatation with resultant
interstitial extravasation of plasma (Bonham et al., 1996;
Widdicombe, 1996b), and by mucus secreted into the airway lumen (Rogers, 2001). All of these changes occur
during airway inflammation as a response to the release of
tachykinins from C-fibre receptors (neurogenic inflammation) (Barnes, 2001), and possibly also as central nervous
system (CNS) reflex changes due to activation of airway
receptors. RARs are also sensitised by decreases in lung
compliance that may occur in airway and lung diseases
(Sellick and Widdicombe, 1970; Bergren and Myers, 1984;
Pisarri et al., 1990; Spina and Page, 1996).
CNS PATHWAYS FOR RAR FIBRES
Although the brainstem respiratory rhythm generator
has been extensively studied for decades, the neuronal
circuitry of cough generation has only recently been ad-
Fig. 7. A putative model of the CNS pathways for the cough reflex,
and their connections with neurones controlling breathing. a: Lower
airway RARs activate relay cells in the brainstem, from which impulses
then pass through a “gate” and activate expiratory premotor and motor
neurones to cause the expiratory effort of cough. b: The RARs also
connect to inspiratory premotor and motor cells. c: The RAR relay cells
(pathway unclear, indicated with a question mark) and the tracheobronchial gate are controlled (facilitated) by the input from SARs, acting via
“pump” cells. d: Input from laryngeal RARs acts in a similar way to that
from lower airway RARs, except that the influence of SARs via the pump
cells is weaker. e: The respiratory pattern generator acts on the inspiratory and expiratory motoneurones, and is affected by inputs from the
tracheobronchial and laryngeal cough pathways. f: Centrally acting antitussive drugs may act primarily by closing the tracheobronchial and
laryngeal gates. From Bolser and Davenport (2002).
dressed in detail. In particular, the elegant studies of
Shannon et al. (1998, 2000) and Bolser and Davenport
(2002) have done much to clarify this difficult subject.
Fibres from RARs first relay in the caudal regions of the
nucleus of the solitary tract (nST). The neurotransmitter
at this site is thought to be glutamate, whereas those for
nociceptive afferents are the tachykinins, substance P,
and neurokinin A (Mazzone and Canning, 2002, 2003).
Other nerve types, such as those from nociceptive C- and
A␦-fibres and SARs, also relay in the nST, and the regions
of representation there probably overlap. The second-order neurones receive multiple inputs from different types
of airway afferent fibre, including SARs (Bonham et al.,
1993; Ezure et al., 1999; Ezure and Tabaki, 2000). For
example, nociceptive C-fibres converge on the RAR relay
cells and facilitate their reflex actions by release of tachykinins—reflexes presumably including cough and bronchoconstriction (Mazzone and Geraghty, 2000; Mutoh et
al., 2000; Mazzone and Canning, 2002). The continuous
low activity from those RARs firing in eupnoea presumably drives the tonic activity of bronchomotor neurones in
the nucleus ambiguus and the dorsal motor nucleus of the
vagus.
If the input from the RARs increases sufficiently, coughing is produced. This involves relay neurones (probably
glutaminergic), with an inhibitory connection from the
SARs via “pump cells.” The relay neurones and the pump
cells act on a “gate” that determines whether the motor act
of coughing is permitted. A simplified diagram of this
system is shown in Figure 7. The models of Shannon et al.
(1998, 2000) and Bolser and Davenport (2002) have three
features that are particularly worthy of comment. First,
the pump cell-gating systems of cough from the trachea
RAPIDLY ADAPTING RECEPTORS (RARS)
7
Fig. 8. Influence of intra-arterial codeine on cough number and
cough phase durations in the cat. Filled circles, cough frequency; empty
triangles, cough total cycle time; open circles, cough inspiratory time;
filled triangles, cough expiratory time. Note that only cough frequency is
affected by codeine. From Bolser et al. (1999).
and larynx have different control systems, supporting the
observation that antitussive agents can have different
actions on coughing from the two regions (Bolser and
Davenport, 2002). Second, although coughing and breathing have a final common integrative path, they can be
dissociated both physiologically (we cannot cough and
breathe at the same time) and pharmacologically by centrally acting antitussive drugs (Bolser and Davenport,
2000). Third, antitussive drugs can affect the components
of cough individually; for example, cough frequency may
be suppressed without changes in cough force or duration
(Bolser et al., 1999; Bolser and Davenport, 2002) (Fig. 8).
There have been extensive studies on the mode of action
of centrally acting antitussives (e.g., Bolser et al., 1994,
1997; Undem and Carr, 2001, Widdicombe, 2002; Mazzone
and Canning, 2002). However, while this subject is of
great importance as regards the central pathways of
RARs, it is beyond the scope of this review.
REFLEXES FROM RARS
Ventilatory Reflexes
The ventilatory reflexes depend on the site of the RARs
stimulated. Those in the epipharynx cause repeated
strong inspiratory efforts—the “aspiration reflex” Widdicombe, 1999, 2001). From the larynx may be elicited either
short, strong expirations (the “expiration reflex”) or coughing (Korpas and Tomori, 1979; Sant’Ambrogio et al.,
1995). Both are assumed to come from RARs, but it is not
known whether there are two populations of RARs or one
population can mediate both reflexes, depending (presumably) on the nature of the stimulus and on central interactions. That RARs (and not C-fibre receptors) from the
larynx mediate cough is evidenced by the fact that when
the extrinsic pathway (recurrent laryngeal nerves) carrying RARs to the larynx is cut, the mechanically induced
cough is abolished. In contrast, when the pathway (superior laryngeal nerves) for C-fibre afferents is cut, the
cough from the larynx is retained (Canning et al., 2000).
From the trachea, mechanical stimuli cause either an
expiratory effort or a cough, while from the larger bronchi
Fig. 9. Augmented inspiratory responses triggered by brief negative
(top record) and positive (lower record) pressure pulses in an anaesthetised rabbit. The pressure pulses can be seen as deflections in the tidal
volume (upper) traces. Lower traces give phrenic nerve discharge. From
Davies and Roumy (1982).
the reflex, at least in the cat, can be 1) a full cough starting
with a deep inspiration, 2) just a deep inspiration (an
augmented breath), or 3) possibly tachypnoea (Widdicombe, 1954b; Korpas and Tomori, 1979). The evidence for
RAR involvement in these reflexes has been abundantly
reviewed (Coleridge and Coleridge, 1986; Karlsson et al.,
1988; Widdicombe, 1998; Sant’Ambrogio and Widdicombe,
2001). It is based partly on 1) correlations between stimuli
and responses, 2) the fact that differential vagal conduction block abolishes the reflexes while leaving the reflex
changes due to C-fibre stimulation largely intact, and 3)
the fact that other potential pathways from the airways
have been shown to have different actions on breathing
(for example, SARs inhibit inspiration and prolong expiration, while C-fibre receptors cause apnoea and rapid,
shallow breathing, and, with selective stimuli, have never
been shown to cause cough).
The ventilatory reflex actions of RARs, presumably in
the bronchi, were studied by Davies and colleagues (Davies et al., 1978; Davies and Roumy, 1982). They discovered that in anaesthetised rabbits, inhalation of high concentrations of sulphur dioxide blocked the activity of SARs
while leaving that of RARs intact. RARs were stimulated
by brief (100 ms) pressure pulses. If given in the inspiratory phase, the stimuli caused an augmented breath (Fig.
9); if applied in the expiratory phase, expiration was
shortened. Thus, the RARs could accelerate breathing and
also cause augmented breaths. A possible involvement of
C-fibre receptors was not eliminated, but seemed implau-
8
WIDDICOMBE
both similar to and different from RARs) have not yet been
determined; many of the definitive experiments have been
conducted with in vitro preparations. The reflexes from
NEBs and the adaptation rates of their afferent fibres
have not been determined, since there are no definite
recordings of action potentials from these fibres (Widdicombe, 2001).
PLASTICITY
Fig. 10. Effect of blocking SARs and vagotomy on the pattern of
breathing of an anaesthetised rabbit. B.P., blood pressure; VT, tidal
volume; PTP, transpulmonary pressure; V⬘, tracheal airflow. First record:
control breathing. Second record: when SARs are blocked by sulphur
dioxide, breathing becomes slower and deeper, but expiration is shorter
and the expiratory pause is lost. Third record: after bilateral vagotomy,
breathing becomes even slower and deeper, and expiration and the
expiratory pause are prolonged, presumably because of the removal of
tonic discharge from the lung RARs. From Davies et al. (1978).
sible. Whereas excitation of C-fibre receptors often causes
rapid shallow breathing after apnoea, it has never been
shown to cause deep inspirations, even with selective
stimuli. Furthermore, C-fibre receptors are not very sensitive to lung volume changes, and would not be expected
to respond to short pressure pulses. These studies also
appear to have clarified a long-standing problem. The
effect of bilateral vagotomy on breathing, i.e., prolongation
of inspiration and expiration, has usually been ascribed to
removal of the action of SARs. However, these receptors
inhibit inspiration and lengthen expiration, and their abolition should lengthen inspiration and shorten expiration.
This is what is seen when SAR activity is abolished by
sulphur dioxide (Fig. 10). Subsequent bilateral vagotomy
lengthens inspiration further, and also lengthens expiration. These results are consistent with a tonic action of
RARs and the reflex effects of vagotomy described above.
Other Reflexes
Other reflexes from RARs include bronchoconstriction,
submucosal gland secretion of mucus, airway vasodilatation, and laryngoconstriction (Coleridge and Coleridge,
1986; Widdicombe, 1986, 1999; Karlsson et al., 1988). Similar reflexes arise from C-fibre receptors. Some of these
reflexes might lead to feedback from effector tissues (bronchial muscle, mucus glands, and mucosal vasculature), as
already described. Reflexes on the heart and vascular beds
generally do not appear to have been established. However, Nishino et al. (1994) described hypertension and
tachycardia in humans when the trachea was stimulated.
Since airway C-fibre receptors cause the opposite reflex
effects, the responses may have been mediated by RARs.
Apparently, the reflexes from nociceptive A␦ fibres in
the epithelium (which, as noted above, have properties
One of the most important recent advances in the study
of airway afferent systems has been the demonstration of
plasticity at receptor, ganglionic, and CNS levels (Carr
and Undem, 2001b; Hoang and Hay, 2001; Canning, 2002;
Undem et al., 2002). A few examples related to RARs are
given here, which may be relevant to the hypersensitive
cough reflex seen in conditions such as asthma (Spina and
Page, 1996). This change may be analogous to primary
hyperalgesia in somatic tissue, wherein the threshold for
a pain-producing stimulus is reduced. There is also a
similarity to allodynia, in which pain may be a response to
stimuli that are not normally pain-producing (Undem et
al., 2002).
At the sensory receptor level, the mechanical sensitivity
of RARs can be increased by administration of histamine
(Sellick and Widdicombe, 1971) or ozone (Joad et al.,
1998), and by allergen challenges in sensitised guinea pigs
(Undem et al., 1993; Riccio et al., 1996b). At the ganglionic
level, both respiratory tract viral infection and allergen
challenge in sensitised guinea pigs can promote the appearance of the tachykinin substance P and neurokinin A
in RAR cell bodies in the nodose ganglion (Fischer et al.,
1996; Canning, 2002; Carr et al., 2002; Myers et al., 2002).
If, as seems likely, these neurones also express the tachykinins in the periphery, there is a potential for RAR sensory complexes to take part in neurogenic inflammation.
Neurotrophins, including nerve growth factor, are probably an intermediary in this change in afferent fibre plasticity. They have been shown to induce tachykinin expression in vagal RARs (Braun et al., 2002; Undem et al.,
2002).
At the CNS level, tachykinin receptors are present in
the primary and secondary neurones of the nTS, and stimulation of these receptors can have a large influence on the
activity of airway reflexes (Mutoh et al., 2000; Canning,
2002). The expression of tachykinins in RARs may contribute to this effect. Tachykinin antagonists, which suppress the cough reflex in experimental animals (Bolser et
al., 1997), could act at this site. At least some are thought
to act centrally. Thus, in the normal CNS, tachykinin
release may affect the reflex actions of RARs, including
cough, bronchoconstriction, and possibly unpleasant sensation; whereas in chronic airway diseases, such as viral
infection and allergic inflammation, a phenotypic change
in the afferent representation of tachykinins in vagal afferents and secondary neurones may produce an additional “tuning” of the airway reflexes.
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