Functional morphology and physiology of pulmonary rapidly adapting receptors (RARs).код для вставкиСкачать
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. LITERATURE CITED Adriaensen D, Timmermans JP, Brouns I, Berthoud HR, Neuhuber WL, Scheuermann DW. 1998. 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