Central nervous pathways and control of the airways

Respiration Physiology 125 (2001) 67–81

Central nervous pathways and control of the airways

David Jordan *Department of Physiology, Royal Free and Uni6ersity College Medical School, Royal Free Campus, Rowland Hill Street,

London NW 3 2PF, UK

Accepted 2 October 2000

Abstract

Neural control of airway muscles and secretions is predominantly by excitatory parasympathetic and non-adrener-gic, non-cholinergic innervations (excitatory and/or inhibitory depending on the species). Functionally distinctafferents effecting airway reflexes terminate in different but overlapping parts of the nucleus tractus solitarius, whereintegration of simultaneously evoked reflex responses occurs. Parasympathetic preganglionic neurones are located inthe dorsal vagal nucleus and nucleus ambiguus, which also contains upper airway motoneurones. These outputneurones receive inputs from the central respiratory network which modify the effectiveness of reflex activity. This isparticularly important since many afferents evoking airway reflexes concurrently modify respiratory drive. Thus, theireffect on the outflow is twofold, a direct reflex effect and an indirect respiratory action and these may facilitate orantagonise one another. Although there is reflex control of individual motor outflows, in some defined situations, e.g.swallowing and coughing a stereotypical pattern of motor outflow is evoked. The neural mechanisms underlying theseaspects of airway control are discussed. © 2001 Elsevier Science B.V. All rights reserved.

Keywords: Airways, central control; Control of breathing, respiratory drive; Muscle, airway smooth; Reflex, integration, NTS;Secretion, airways

www.elsevier.com/locate/resphysiol

1. Introduction

In any description of control of the airways it isnecessary to consider the control of airway diame-ter, and hence airway resistance, and in addition,the control of mucous secretion. There is a wealthof data dealing with the physiology and pharma-cology of airway smooth muscle both at a singlecell level and in vivo. There is much less dataconcerning the control of airway secretions. This

imbalance arises partly form the perceived relativemedical importance of the two aspects, but alsofrom the fact that discrete experimental prepara-tions of airway muscle have been easier to define— the small volumes and prolonged duration ofthe secretory responses have made in vivo reflexexperiments relatively difficult to perform. Whatis known about the peripheral control of airwaysecretions has been reviewed recently (Rogers,1997) and will not be repeated here. Thereforemuch of what follows will concentrate on centralcontrol of airway muscles, and although many ofthe underlying principles are likely to apply also

* Tel.: +44-20-78302771; fax: +44-20-74331921.E-mail address: [email protected] (D. Jordan).

0034-5687/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.

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D. Jordan / Respiration Physiology 125 (2001) 67–8168

to control of secretory glands, the details arelikely to vary. In addition, smooth muscles in thepharynx, larynx, trachea, and bronchioles are notnecessarily controlled in the same manner and it isknown that there are interspecies differences, soalthough some general principles are described,there are likely to be individual differences, andsome of these will be highlighted.

The smooth muscles of the airways are sub-jected to multiple controls. Depending on whetherthey are intra- or extrathoracic, the muscle tonewill or will not be altered by physical changeswithin the thorax — during inspiration the smalldistensible airways dilate due both to the loweredintrathoracic pressure and the traction forces ex-erted by the inflating alveoli. In addition, endoge-nously secreted mediators, both dilator andconstrictor, also alter airway tone. These mayoriginate from intrinsic airway cells such as mastcells or epithelial cells, or may be from extrinsicsources such as eosinophils and neutrophils, orcirculating within the blood stream (see Barnes etal., 1998; Leff, 2000). In addition to these hu-moral controls there is a powerful neural controlof airway muscles and secretory glands. Reflexchanges in airway resistance and maintenance ofresting airway tone are mediated via the choliner-gic parasympathetic smooth muscle innervation.Whilst sympathetic nerves innervate the airwaysof some species, their role in day to day airwaycontrol is much less important. Finally, a non-adrenergic, non cholinergic (NANC) innervationof airway smooth muscles has been identified inmany species and although it forms the predomi-nantly inhibitory control of smooth muscles, thereare reports of excitatory effects also (Laitinen andLaitinen, 1997). Interestingly, evidence is now ac-cumulating that abnormalities and/or imbalancesin these NANC systems may underlie some air-way disease states (Smart and Casale, 1997).

Airway smooth muscle is tonically active underresting conditions. Reflex constrictions and relax-ations are normally mediated by increases anddecreases in vagal cholinergic activity, respec-tively. Bronchodilation may also be evoked byincreased NANC nerve activity. There are numer-ous sensory afferents, both within and extrinsic tothe airway, that can evoke reflex changes in

smooth muscle activity (see Coleridge et al., 1989;Jordan, 1997 for review). Activation of both pe-ripheral and central chemoreceptors evoke va-gally-mediated bronchoconstrictions. Moderatelung inflations, which activate slowly adaptinglung stretch afferents (SARs) reduce vagal bron-chomotor activity whereas larger lung inflations,which activate rapidly adapting lung stretch affer-ents (RAR) and bronchopulmonary C-fibre affer-ents evoke bronchoconstriction. Similar airwayconstrictions can also be induced by inhalation ofdust or mechanical stimulation of the tracheal andlaryngeal mucosa. Finally, dilation of the airwaysfollows stimulation of the arterial baroreceptorsand during activation of Group III and Group IVafferents arising in skeletal muscle and activatedduring exercise. This latter effect can be mimickedby activation of regions of the hypothalamuswhich evoke a cardiorespiratory pattern of re-sponse typical of muscular exercise (McCallister,et al., 1988).

The tone that airway muscle exhibits at rest isdue in most species to vagally mediated constric-tor activity since it can be abolished by atropine(Mitchell et al., 1985). The neural origin of thisactivity is likely to be a summation of the differ-ent afferent inputs described above, many ofwhich have ongoing discharge at rest, and someinfluences from central nervous sites. Whilst muchof this work was carried out originally on anaes-thetised cats and dogs, it is clear that there aremarked species differences in some reflex re-sponses (Nishino et al., 1996; Jordan, 1997 fordetails). For example, tracheal irritation evokedcoughing in cats, dogs and humans, but not inferrets or mice. Similarly, the relative effectivenessof chemical vs mechanical activation of trachealand laryngeal mucosa in evoking reflexes variesbetween species (Karlsson, 1996). Finally, thepresence of anaesthetic in these studies will havemodified the responses evoked. These factorsmust be taken into account when animal modelsof human pathophysiology are developed. Toni-cally active peripheral excitatory and inhibitoryinputs arise from non-myelinated airway afferentsand SARs, respectively. In addition, the level ofarterial PO2

and PCO2provide, via peripheral and

central chemoreceptors, another excitatory drive

D. Jordan / Respiration Physiology 125 (2001) 67–81 69

(Widdicombe, 1961). Whilst some of this drivewill be a direct effect of the chemoreceptor affer-ent input, there will, in addition be an indirectaction via their influence on the level of centralrespiratory drive which has a profound influenceon vagal bronchoconstrictor activity (Mitchell etal., 1985; Jordan 1997; see later). The other cen-tral sites contributing to tonic bronchomotordrive have not been well documented although itis known that the hypothalamus can contribute tothe bronchodilatation of exercise.

As both sensory afferent inputs and centralregions can influence bronchmotor tone, in orderto fully understand the central mechanisms re-sponsible for controlling airway function it isnecessary to consider not only the central path-ways accessed by sensory afferents evoking bron-chomotor changes, but also how these pathwaysare organised in relation to other central nervousregions. In particular, the central nervous sub-strate responsible for generation and control ofcentral respiratory drive is of prime importance inthis respect.

2. Airway afferent terminations

Primary visceral afferents effecting airway refl-exes terminate in the caudal two thirds of thenucleus of the tractus solitarius (NTS), around thelevel of the obex (see Jordan and Spyer, 1986;Jordan 1997; Taylor et al., 1999 for review).Anatomical studies delineated the overall terminalfields of such vagal and glossopharyngeal afferentfibres. In all species studied vagal afferents termi-nate predominantly in the caudal two thirds ofthe NTS and glossopharyngeal afferents terminatein the rostral two thirds, an area of overlapoccurring around obex level. In addition, it isclear that although there is a wide distribution ofterminals within the NTS, there is some topo-graphical arrangement based on organ of innerva-tion. However, it has required electrophysiologicalstudies to investigate the afferent fields of func-tionally distinct primary afferents. Using an-tidromic mapping the terminations of rapidly-and slowly- adapting pulmonary stretch receptorafferents, pulmonary C-fibre afferents and

bronchial C-fibre afferents have been delineated(Fig. 1). Terminals of RAR afferents are concen-trated in the region around obex level with thedensest innervation being found in the commis-sural subnucleus and a less dense input to theventrolateral and medial subnuclei. This distribu-tion is caudal to that of SARs which tend toproject to regions rostral to obex, mainly to themedial subnucleus with some input to the lateraland ventrolateral NTS. The termination of C-fibreafferents, whether they originate within thebronchial or pulmonary regions is rather similar.At obex level, they project to the medial subnu-cleus primarily but not to the lateral or ventrolat-eral subnuclei. Caudal to obex they projectbilaterally within the commissural nucleus.

Intracellular labelling of single, physiologicallyidentified afferent fibres in cats has recently al-lowed direct visualisation of SAR, RAR andmyelinated laryngeal afferent terminals. The ven-tral, ventrolateral, intermediate and interstitialNTS had SAR teminals and these were foundmore rostral than the RAR terminals located inthe interstitial, dorsal and dorsolateral NTS.RAR terminals were not seen in the ventral andventrolateral NTS, the major loci of laryngealafferent terminations (Bellingham and Lipski,1992). In addition, some laryngeal afferents werealso seen in the dorsal, dorsolateral, medial andinterstitial subnuclei overlapping the areas of pro-jection of RAR terminals. The organisation of thelaryngeal afferent terminations within the intersti-tial subnucleus of rats has been studied in detail(Mrini and Jean, 1995) as this region is thought tobe involved in swallowing and respiratory reflexes(see Section 8.1).

3. Organisation of the NTS

It is obvious from these studies that althoughfunctionally different afferent fibres have somedistinct regions of projection within the NTS,there is also significant overlap in other regions oftermination. Functional reflex studies have sup-ported this view. Electrolytic or chemical lesions,or disruption of synaptic transmission within dis-crete areas of the rat NTS have been shown to


produce defined deficits. Blockade of neurotrans-mission in the medial NTS by injections of cobaltchloride or non-NMDA receptor antagonists at-tenuated SAR-induced apnoea (Bonham et al.,1993). Similar microinjections of cobalt chlorideor K+ channel blockers into the commissuralnucleus abolished the respiratory and cardiac ef-fects of stimulating pulmonary C-fibre afferents(Bonham and Joad, 1991; Butcher and Paton,1998). As yet, there are no similar studies onmodification of airway reflexes evoked by theseafferents though there is little reason to think thatthe underlying organisation of these reflexesshould be different to those affecting cardiac orrespiratory changes.

Whilst these gross microinjection studies givean indication of the functional heterogeneity thatoccurs within the NTS, only recent electrophysio-logical studies have begun to unravel the complexinteractions occurring within the neural substrateof the NTS. Whilst much of this work was hasbeen done on cats, similar studies in rats have

shown a very similar neural organisation. It wasoriginally believed that although convergence andinteractions between different functional afferentsoccurred in the NTS, this was only to a limitedextent (Jordan and Spyer, 1986). However, withthe recent use of intracellular recordings a greateramount of convergence and interaction has beendemonstrated (see Jordan, 1997 for detailed re-view). As will become apparent, these interactionsare not indiscriminate, but have a functional ba-sis. Even an early study demonstrated that al-though some NTS neurones received convergentinputs from both pulmonary and cardiac sensoryafferents, the inputs were segregated according tothe afferent conduction velocity such that myeli-nated and non-myelinated inputs did not convergeon the same neurones. This led us to suggest thatthe basis of the organisation is one of homeostaticversus defensive reflex interactions (Coleridge etal., 1991) and further data to support this viewhas recently been published. NTS cells receivinginput from atrial volume receptors are unlikely to

Fig. 1. Summary of the major sites of termination within the NTS of sensory afferents involved in airway control, as determinedby antidromic mapping and electrophysiological tracing. The relative densities of ipsilateral (�) and contralateral () regions oftermination are shown by the number of dots. The most extensive terminal fields are shaded. Reproduced with permission fromJordan (1996).


Fig. 2. Diagrammatic representation of the organization of the second order neurones within the NTS (shaded) involved inintegrating afferent inputs regulating airway responses. Neurones receiving inputs from slowly- (SAR) and rapidly-adapting (RAR)lung stretch receptor afferents and superior laryngeal nerve afferents (SLN) are illustrated. Demonstrated and suggested interactionsare illustrated. Solid lines show excitatory interactions, dotted lines inhibitory effects. See text for full description of the details.Abbreviations: CIA, central inspiratory activity; glu, glutamate; gly, glycine; Ib, inspiratory b neurone; L, 2nd order laryngealneurone; lat PBN, lateral parabrachial nucleus; P, 2nd order SAR neurone; R, 2nd order RAR neurone; VRG, ventral respiratorygroup. Modified and reproduced with permission from Jordan (1996).

receive input from cardio-pulmonary C-fibre af-ferents (Hines et al., 1994) whereas those cellsreceiving veratridine-sensitive cardiac afferent in-put also received input from carotid bodychemoreceptors and/or pulmonary C-fibres, butnot from arterial baroreceptors (Silva-Carvalho etal., 1998). Similarly, a high proportion of NTScells receiving pharyngoesophageal inputs werealso activated by carotid chemoreceptors (Patonet al., 1999). In a detailed study Mifflin (1996)reported NTS cells receiving convergent inputfrom arterial baroreceptors, carotid chemorecep-tors and/or laryngeal mechanoreceptors and someof these inputs were thought to be monosynaptic.

Despite this convergence, there must be somefunctional organisation within the NTS that al-lows independent reflex actions to occur, thoughobviously, under physiological conditions thisrarely happens. Usually, one or more sets ofafferent fibres will be activated, and it is likelythat there are modulatory influences from otherbrain regions impinging on the nucleus and modi-fying the effectiveness of the individual reflexpathways. These interactions will occur at thesecond- or higher order neurones within the NTS(Fig. 2).

Regarding slowly-adapting lung stretch recep-tor afferents (SARs), these target two differentgroups of NTS neurone. ‘Pump’ (P) cells appearto be the 2nd-order neurones of the Hering-Breuer reflex since they receive monosynaptic in-

put from SARs and have a firing rate whichclosely mirrors the degree of lung inflation andthe activity of SARs in cats (Berger, 1977). Inrats, these cells, in addition, receive central res-piratory drive inputs (Miyazaki et al., 1998). Inaddition, SARs make monosynaptic excitatoryconnections with Ib cells, a subgroup of the dorsalrespiratory group of inspiratory neurones locatedin the ventrolateral NTS (von Euler, 1997). Al-though both P cells and Ib cells are 2nd orderSAR cells, they do not receive this input exclu-sively. Ib cells are inspiratory firing neurones andthus receive input from the central respiratorypattern generator, and in addition, they are alsoexcited during gasps and may therefore also re-ceive input from rapidly-adapting lung stretchreceptor afferents (RARs). P cells are also not ahomogenous group. They are found in twoanatomically distinct areas with different projec-tion patterns — those in the dorsal/dorsolateralNTS have axons projecting to the contralateralmedial and commissural NTS (the location ofRAR terminations) whilst those in the ventral/ventromedial NTS have few contralateral projec-tions, terminating predominantly in the region ofipsilateral ventral respiratory group in the nucleusambiguus (Davies et al., 1987; Ezure and Tanaka,1996). Some also have axons ascending rostrallyto the pons where they are thought to terminatein the lateral parabrachial and Kolliker-Fuse sub-nuclei (Ezure et al., 1998). In addition to their


SAR inputs, some P cells also receive input fromlaryngeal afferents (Berger, 1977). Since SARsand laryngeal stimulation have opposite effects onairway smooth muscle, it is unlikely that these Pcells receiving such convergent input are responsi-ble for SAR effects on airway resistance whichsuggests that those P cells receiving only SARinput, or Ib cells as mediating the airway effects.

Laryngeal inputs, in addition to activatingsome P cells monsynaptically, also exhibitmonosynaptic excitation of some NTS inspiratoryneurones and other non-respiratory firing NTSneurones, at least in cats. These have been foundin both the ventral NTS where many laryngealafferent terminate (Bellingham and Lipski, 1992)and in the commissural, dorsal and medial NTS(Mifflin, 1993). This heterogenous laryngeal inputmay reflect the diversity of laryngeal afferents andthe reflexive effects they mediate which encompassnot only upper and lower airway patency andsecretions, but swallowing, coughing, respiratorypatterns and cardiovascular responses.

The 2nd order neurones receiving RAR inputare located in the ipsilateral caudal medial NTSand bilaterally in the commissural region (Kubinand Davies, 1988; Lipski et al., 1991). This over-laps but is mainly caudal to the location of P cells.Indeed, lesions of this region abolish the reflexeffects of RAR activation but not the Hering-Breuer reflex (Ezure et al., 1991). Unusually, thesecaudal RAR cells appear to receive a bilateralvagal afferent input in cats (Lipski et al., 1991)but not in rats (Ezure et al., 1999) and in parallelto some P cells, many of these RAR neuroneshave axons projecting rostral to the pons (Ezureet al., 1991). RAR activation of these cells ismediated by glutamate (Bonham et al., 1993)acting on non-NMDA receptors (Ezure et al.,1999). RAR neurones are not simple relay neu-rones, like P cells, they too are susceptible toother inputs. Many show modulation of theirfiring pattern in synchrony with central respira-tory — firing being reduced during inspirationand early expiration (Lipski et al., 1991; Ezure etal., 1999). Intracellular recordings indicate thatthis is due to a strychnine-sensitive inhibitoryinput during inspiration and early expiration. Inaddition, they receive a tonically active bicu-

culline-sensitive inhibitory input (Ezure et al.,1999) and an inhibitory input from P cells (Ezureand Tanaka, 2000).

Much less is known about the central integra-tion of ‘defensive’ afferents. In rats, neuronesreceiving bronchial or pulmonary C-fibre afferentinput are located in the commissural and caudalmedial NTS (Wilson et al., 1996; Jeggo et al.,2000; Sevoz-Couche et al., 2000). Stimulation ofcardiopulmonary afferents has been shown to ex-cite or inhibit different populations of NTS cells(Sevoz-Couche et al., 2000). In addition, theyinhibit inspiratory neurones in the ventrolateralNTS of both rats and cats (Jones and Jordan,1993). The input to NTS neurones appears to bemediated by serotonin acting on 5-HT2 (Sevoz-Couche et al., 2000) and 5-HT3 receptors (Jeggoet al., 2000) and is markedly increased in guineapigs chronically exposed to ‘passive’ smoke (Mu-toh et al., 2000).

4. Airway motor innervation

Airway patency is controlled by the striatedmuscles of the pharnyx and larynx and thesmooth muscles of the trachea and lower airways.These airway smooth muscle cells are innervatedby excitatory parasympathetic fibres travelling inthe vagus and glossopharyngeal nerves. This pre-dominant cholinergic control of airway smoothmuscle at the level of the neuroeffector junctionhas been reviewed in detail recently (Barnes, 1997;Fryer, 1997; Jordan, 1997) (Fig. 3). Although inmost species there is little, if any sympatheticinnervation of the smooth muscle, there are non-adrenergic non-cholinergic (NANC) excitatoryand inhibitory systems (see Black, 1997).

Anatomical and electrophysiological studieshave delineated the central origin of the motorfibres innervating the airway. Vagal preganglionicneurones are found in both the dorsal vagal nu-cleus (DVN) and nucleus ambiguus (nA), pre-dominantly ipsilaterally, with a few neuronesfound in the reticular formation between the two(intermediate zone). The relative importance ofthe two nuclei varies from species to species (Tay-lor et al., 1999) but both consist of a topographi-


cally arranged longitudinal column of neurones(see Jordan, 1997; Taylor et al., 1999 for review).The nA is a diffuse collection of cells extendingfrom the level of the facial nucleus caudal to C1

and has been described in most detail in the rat.Its dorsal division (compact, semi-compact andloose divisions from rostral to caudal) comprisesthe somatomotor innervation of the pharynx and

Fig. 3. Diagrammatic representation of parasympathetic (vagal) and sympathetic innervations of airway smooth muscle andsecretory glands. Vagal preganglionic neurones (VPNs) receive reflex inputs and inputs from brainstem inspiratory (I) and expiratory(E) networks. They synapse in the parasympathetic ganglia (PG) located within the airway walls. Sympathetic preganglionicneurones (SPNs) in thoracic spinal cord synapse in sympathetic ganglia (SG) or release adrenaline from the adrenal medulla. Thiscan act on b-adrenergic receptors to stimulate secretion and relax the smooth muscle. Vagal excitatory effects are mediated bypostjunctional M3 receptors but the release of acetylcholine is modulated by inhibitory prejuncional M2 autoreceptors. Cell bodiesof preganglionic neurones are the site of facilitatory M1 and nicotinic cholinergic receptors. Reproduced with permission fromJordan (1997).


thoracic viscera whilst the ventral division is com-prised of parasympathetic preganglionic neurones.Although there is some topography within theDVN, it is not as well defined as the nA. Withinthe nA neurones innervating different airwaystructures are separated. Rostrally, pharyngealneurones are located in the semi-compact groupand at the same level oesophageal motoneuronesare located in the compact nucleus. More caudal,laryngeal motoneurones are found mainly in thesemi-compact and loose formations with theparasympathetic preganglionic neurones being re-stricted to the external formation. Neurones in-nervating the trachea are found in the compactand external formations of the nA but not withinthe DVN. In cats, a similar topographical organi-sation has been described, though some speciesdifferences do exist. Notably, laryngeal motoneu-rones were found mainly in the nA, but somewere also localised to the rostral DVN. Trachealmotoneurones were found in the same nA sites aslaryngeal neurones, but were, in addition, foundmore caudally in the nA, behind the obex, and inthe DVN at obex level. In those studies mostbronchial motoneurones were located within theDVN, with some being seen in the rostral parts ofthe nA. However, others have demonstrated thatbronchial neurones were found predominantly intwo groups at the rostral and caudal poles of thenA, and these outnumbered those located in thelateral DVN. These studies relied on retrogradelabelling neurones with tracers placed on cutnerves or injected into organs of innervation. Thiscan provide misleading information when the tis-sue is not homogenous. In the larynx, for exam-ple, the individual laryngeal muscles havedistinctive roles and their pattern of activationcan alter depending on the reflex evoked. A muchmore detailed topography of motoneurones inner-vating individual laryngeal muscles has been de-scribed by injections into individual laryngealmuscles and a detailed description has been pub-lished (see Jordan, 1997).

Laryngeal afferents travelling in the superiorand inferior laryngeal nerves terminate in theNTS. Stimulation of the laryngeal mucosa evokesreflex responses in recurrent laryngeal motoneu-rones located in nA and although direct NTS-nA

connections have been identified in anatomicaltracing studies, multisynaptic pathways for spe-cific reflexes could not be studied by these meth-ods. Recently, the use of c-Fos labelling has beenused to map brainstem neurones in cat activatedduring mechanical stimulation of the laryngealmucosa (Tanaka et al., 1995). Rostral to obex,neurones were labelled in the medial, ventral dor-solateral, ventrolateral, interstitial and intermedi-ate subnuclei (most in medial and interstitial).Caudal to obex labelled neurones in commissuraland dorsolateral subnuclei. In the nA, many la-belled neurones were found, predominantly indorsal and lateral nA but in addition, a fewneurones ventral to the nA. There were also la-belled neurones in the spinal trigeminal nucleusand some cells in lateral tegmental field. Since themajority of labelled cells were in NTS and nA, itis likely that most laryngeal reflexes use a directNTS-nA pathway rather than a multisynapticone.

5. Activity of motoneurones innervating theairways

Although anatomical studies have suggested atopographical arrangement of airway motoneu-rones within the brainstem, only neurophysiologi-cal experiments can address questions regardingthe control of outflows of different function. Hy-poglossal and laryngeal motoneurones innervatingthe tongue, pharynx and upper airway have beenmost studied. There is less information on activityof vagal preganglionic neurones innervating air-way smooth muscle and secretory glands.

Activation of hypoglossal and laryngeal mus-cles are crucially important in maintaining thepatency of the upper airways by opposing thenegative intrathoracic pressure produced duringinspiration (Nolan, 1998) and individual laryngealmuscles have other specific functional roles. Theongoing activity and synaptic inputs to the differ-ent hypoglossal and laryngeal motoneurones hasbeen reviewed recently (Jordan, 1997). Many ofthese outflows have respiratory related activity,different hypoglossal neurones firing during inspi-ration, post-inspiration or stage II expiration.


Both laryngeal and peripheral chemoreceptor in-puts powerfully excite these neurones but it isunclear if these are direct effects or via activationof neurones in the respiratory network (see later)since these stimuli particularly enhance post-in-spiratory discharges in these neurones. In addi-tion, lung inflation inhibits these neurones so thatduring airway obstruction they will be disinhib-ited. Laryngeal neurones innervate a variety ofmuscles of widely differing functions. It is notsurprising then that their activity profiles differmarkedly one from another. Most exhibit respira-tory-related patterns of activity which is due toexcitatory and/or inhibitory inputs from neuroneswithin the respiratory network, particularly post-inspiratory neurones. Stimuli which provoke in-creased post-inspiratory activity such as arterialchemoreceptors, laryngeal afferents, J-receptorsand airway irritation provide powerful stimuli tothese whereas lung inflation can have an in-hibitory or excitatory influence. Although infor-mation on the detailed organisation ofhypoglossal and laryngeal control mechanisms issparse, even less is known about the control ofvagal preganglionic neurones innervating airwaysmooth muscles and secretory glands. Early stud-ies recorded activity in vagal fibres innervating thelungs and trachea of cats and dogs. The activityof these fibres has complex relationships to res-piratory pattern, they are excited by arterialchemoreceptors and airway irritation, and inhib-ited by arterial baroreceptors and moderate de-grees of lung inflation (overinflation or deflationincreasing activity presumably by activating air-way irritant receptors) (Widdicombe, 1961; Jew-ett, 1964; Widdicombe, 1966). More recently,recordings have been made from the cell bodies oforigin of these fibres in the DVN and nA. Thosewithin the lateral DVN had non-myelinated axonsand little, if any, ongoing activity and were unaf-fected by lung inflation (Ford et al., 1990) whilstthose in the nA had small myelinated axons andusually had ongoing activity, firing during inspira-tion (McAllen and Spyer, 1978; Jordan et al.,1986). Due to the bias of recording from larger,less fragile axons, the earlier fibre recordings wereprobably biased towards this latter group. Theseprobably mediate reflex vagal bronchoconstriction

since they are activated by reflex inputs whichevoke bronchoconstriction and activation of smallmyelinated vagal efferents that can evoke in-creased airway resistance (McAllen and Spyer,1978). In some species such as the rabbit activa-tion of non-myelinated vagal efferents can alsoproduce bronchoconstriction (see Jordan, 1997)so it is possible that bronchomotor neurones arealso found within the DVN. Those neurones/fibres with different firing patterns may be mediat-ing secretomotor or vasomotor activity. Theeffects of respiration and lung inflation togetherresult in a complex discharge in these neurones,depending upon the relative magnitude of theseopposing drives. At eupneoic levels of sponta-neous ventilation, when lung inflation and centalrespiratory drive are synchronised, the output willbe a balance of the inhibitory/excitatory effectsrespectively with activity correlated with centralinspiratory drive predominating. This is manifestas increased tracheal smooth muscle tension dur-ing inspiration (Mitchell et al., 1985). Activationof sensory input may have a variety of effectssince many also alter central respiratory drive, theresult being a composite of this indirect respira-tory input and any direct effect of the sensoryafferents. Thus stimuli which enhance inspiratorydrive tend to constrict the airways whilst thosewhich promote expiration tend to dilate (Mitchellet al., 1985; Jordan, 1997).

6. Neurotransmission in airway ganglia

Although the location, activity and control ofpreganglionic fibres has been described, it cannotbe assumed that this activity is faithfully transmit-ted to the effector tissue. It is becoming clear thatautonomic ganglia are not 1:1 relays but indepen-dent sites of integration. There are pre- and post-synaptic mechanisms involved in modulation ofganglionic transmission, and numerous pharma-cological studies have identified a variety of classi-cal and novel neurotransmitters and modulatorsinvolved (Fig. 3). This area has been reviewed indetail recently (Fryer, 1997; Jordan, 1997; Undemand Myers, 1997; Myers, this issue) so readers aredirected to those for discussion.


7. Interactions with the central respiratory system

It is clear from the discussion above that al-though motor outflow to the respiratory tract iscontrolled by specific reflex pathways, it may alsohave inputs from components of the central res-piratory network. Since many of the sensory af-ferents which provide reflex input to themotoneurones also evoke changes in respiratorydrive, it is important to consider how these influ-ences interact as this will be a major determinantof the final motor output. That the level of res-piratory drive is an important component of on-going vagal bronchomotor tone is apparent fromthe observation that hyperventilation to centralapnoea reduced tracheal smooth muscle tensionto that seen following vagotomy (Mitchell et al.,1985). The interactions between respiration andcardiorespiratory reflexes are very old in a phylo-genetic sense, the neural substrate being conservedin most vertebrates. The topographical similaritiesand apparent evolution of these interactionsthrough the major vertebrate groups, includingmammals, has been thoroughly reviewed recently(Taylor et al., 1999) so only a summary will beincluded here.

Respiratory modulation of motor activity andthe effectiveness of airway reflexes could be im-posed at the level of the afferent input the NTS,at the motoneurones in the DVN and nA, oranywhere in the pathway between. Since the dor-sal respiratory group is close to the site of termi-nation of afferents within the NTS (von Euler,1997) and the ventral respiratory group within thevicinity of airway motoneurones and vagal pre-ganglionic neurones within the nA, these wouldappear to be two prime sites for modulation tooccur. At the level of the NTS, modulation couldbe imposed presynaptically on the afferent termi-nals themselves, or at the numerous postsynapticsites within the reflex pathways. So far, there isevidence that afferents arising in the airways orlungs are subjected to presynaptic control fromthe central respiratory network and other airwayafferents. Also modulation occurring within theNTS may be of a postsynaptic nature. As de-

scribed earlier, some NTS cells (P cells) receiveconvergent laryngeal and SAR input (Berger,1977) whilst others (Ib neurones) receive inputsfrom both laryngeal afferents and the central res-piratory network (Fig. 2). These could provide forsome respiratory-related modulation of laryngealreflexes. However, there is also a population ofcells which receive laryngeal but no detectablerespiratory-related input (Mifflin, 1993; Dawid-Milner et al., 1995) so clearly, at least someafferent input can pass the NTS without a signifi-cant degree of respiratory modulation. Similarly,SAR afferents have inputs to both respiratorymodulated (Ib neurones) and non-respiratorymodulated neurones (Berger, 1977). In contrast,many of the cells receiving RAR input have res-piratory modulation of their firing (Lipski et al.,1991; Ezure et al., 1999) and some also receiveinhibitory input from P cells (Ezure and Tanaka,2000) so it would not be surprising to find thesereflexes showing a degree of respiratorymodulation.

There is little information regarding the originof respiratory related inputs to the airway mo-toneurones. Intracellular recordings indicate thathypoglossal and laryngeal motoneurones receivesynaptic input from components of the respira-tory network (Withington-Wray et al., 1988;Richter and Spyer, 1990) but the origins of theseinputs has not been delineated. Vagal pregan-glionic neurones within the DVN receive excita-tory input from pulmonary C-fibre afferents butnot from SARs or central respiratory drive (Joneset al., 1998). Within the nA however, neuronesconsidered to be bronchomotor in function firepredominantly during inspiration (McAllen andSpyer, 1978; Jordan et al., 1986). It is unclearwhether this is the result of an inspiratory-relatedexcitatory input and/or an expiratory-related in-hibitory input. However, the latter is a possibilitysince these cells are found in the rostral andcaudal nA, at the level of the rostral and caudalgroups of expiratory cells (Jordan et al., 1986). Aconverse but analogous situation exists for car-diomotor preganglionic neurones in the nA whichhave an expiratory firing pattern (McAllen andSpyer, 1978), are found in the intermediate nA at


the level of the inspiratory neurones, and havebeen shown to receive a powerful inspiratory-re-lated inhibitory input in addition to a post-in-spiratory excitatory input (Gilbey et al., 1984).

Whatever the degree of respiratory modulationoccurring at central sites, it is clear that theairway ganglia also help to augment such rhyth-mical activity. As described above, these act asintegrating sites in their own right. The frequencyof the e.p.s.p.s they receive varies with the respira-tory cycle, which therefore determines the degreeof summation and hence the output of the post-ganglionic fibres (Mitchell et al., 1989).

The importance of these interactions is suchthat the respiratory effects evoked by a sensoryinput may completely override the direct effects ofthe stimulus. This was powerfully demonstratedby Haxhiu et al. (1989) who showed that stimula-tion of pulmonary C-fibre afferents during apnoeaevoked increases in tracheal smooth muscle ten-sion, as expected, but if such stimuli were appliedduring spontaneous ventilation an apnoea wasevoked and its associated tracheal relaxation to-tally masked the primary constrictor response.This is not unlike the well documented effects ofrespiration on vagal outflow to the heart wherebythe primary bradycardia evoked during the arte-rial chemoreceptor reflex is attenuated or evenreversed to a tachycardia when the inspiratoryenhancing component of the reflex is large. Al-though, a clear correlation between the levels ofinspiratory drive and bronchoconstrictor activityexists, the linkage can be broken under certaincircumstances. During exercise for example, al-though inspiratory drive increases, there is bron-chodilation. It is unclear how this occurs. It ispossible that afferent input evoked during exercisealters input from the central respiratory network,or other oscillatory networks may come into play.It has been suggested that multiple respiratoryoscillators exist within the brainstem (Richardson,1988). In addition to the eupneoic pattern genera-tor, a phylogenetically older and slower oscillatorfor the branchial musculature (Taylor et al., 1999)and a newer, faster one related to gasping (St.John, 1990) have been described. These may nor-mally be entrained but under certain circum-stances the balance between them may alter.

8. Patterning of motor outflow

Although reflex control of individual motoroutflows by airway afferents occurs, in somedefined situations a defined pattern of motoroutflow is evoked. This can be seen, for example,during swallowing, coughing, sneezing and vomit-ing. In each case the response is triggered as aresult of a variety of afferent inputs, but oncetriggered, it occurs as an all or none response. Inrespect of airway control, the patterns of activityoccurring during swallowing and coughing havebeen subject to most investigation.

8.1. Swallowing

The motor pattern of swallowing, triggered byinputs from the pharyngeal and laryngeal mucosa,is a stereotyped pattern of behaviour. Once trig-gered, no further input is required suggesting thatthere is a ‘central pattern generator’ for swallow-ing (see Jean, 1990). Similar ‘motor pattern gener-ators’ have been postulated to underlie therhythmical activity in motor nerves during fictivelocomotion (Windhorst, 1996). ‘Swallowing-re-lated’ neurones have been located in and aroundboth the NTS and nA (Jean, 1990; Jean et al.,1993). Recently, Umezaki et al. (1998) reported incats that ‘swallowing-related’ neurones could beseparated into three types. Sensory-relay type neu-rones located in the NTS, interneurones in theparvocellular reticular formation ventral to theNTS, and motoneurones in the nA. During swal-lowing closing reflexes are important in protectingthe airway from entry of foreign material. Whenadductor responses are recorded to laryngealstimuli 2 distinct responses occur, an early ipsilat-eral response and a longer latency bilateral re-sponse. The later response is amenable toconditioning from afferent stimuli, and this mayoccur at the level of the NTS where Sessle(1973a,b) has demonstrated both pre- and postsy-naptic interactions on laryngeal afferent inputs.However, central conditioning of these responsesis also apparent. Barkmeier et al. (2000) havedemonstrated that during swallowing in awakehuman subjects the late response evoked by SLNstimulation was markedly attenuated whereas the


early response was unaffected. This would suggestthat the two responses are mediated by separatecentral pathways. The site of such modulation isunknown, but must be central since afferentnerves were stimulated electrically. The NTS andnA are obvious candidates but cortical sites arealso possible — ‘swallowing-related’ neuroneshave been recorded in the lateral pericentral gyrusand tongue primary motor cortex (Martin et al.,1997) and microstimulation of the face region ofthe primary motor and somatosensory corticesand a deeper structure (cortical masticatory re-gion) evoked swallowing movements (Martin etal., 1999). Although at some sites swallowing wasevoked as part of other facial and masticatorymovements, at others, particularly in the deepcortical area and an area in the lateral part of theface motor cortex, swallowing alone was evokedby low intensity cortical stimuli. These corticalareas are suggested to participate in the initiationof voluntary swallowing movements as well asmodulating those evoked by laryngeal sensoryinput (Barkmeier et al., 2000).

8.2. Coughing

Coughing, a stereotyped pattern of abdominal,respiratory and airway muscle activation can beevoked by laryngeal and tracheobronchial affer-ents. It is clear that cough is evoked by stimula-tion of rapidly adapting receptors (RARs), butthere is still debate whether C-fibre afferents arealso effective (Fox, 1996; Sant’Ambrogio andSant’Ambrogio, 1996). Additionally, activation ofslowly adapting lung stretch receptor afferents(SARs) although not evoking cough, potentiatesthe effects of other stimuli. It is likely that theintegration of these inputs occurs within the NTSbut no neural substrate responsible for cough has,as yet been identified (see Jordan, 1996). Nostudies are reported to have tested whether NTScells respond to both RAR and C-fibre activationbut the medial NTS is a common site of termina-tion. However, laryngeal fibres do not seem toproject here — their terminations overlap thoseof SARs and are distinct from those of RARs(Fig. 2). One group of P cells receive input fromboth SARs and laryngeal afferents (Berger, 1977)

and project to the contralateral commissural nu-cleus where RAR cells are located (Kubin andDavies, 1988; Lipski et al., 1991). However, in-stead of providing an excitatory input to RARcells, it has recently been demonstrated that manyRAR cells are inhibited by activation of P cellsduring lung inflation Ezure and Tanaka, 2000). Ib

neurones, a subgroup of the dorsal respiratorygroup in the ventrolateral NTS fire during inspira-tion and in addition, during expiration they canbe activated by lung inflation (von Euler, 1997).This is due, at least in part, to a monosynapticinput from SARs but since the response adapts,requires relatively large inflation volumes and thecells are activated during a gasp, it is possible thatthey also receive RAR input. If this were the case,then these would be ideal candidates for mediat-ing cough responses since some have also beenshown to receive a short latency laryngeal input.On the other hand, both the central respiratorynetwork in the ventrolateral medulla and non-res-piratory neurones in the caudal NTS have beenshown to be activated during fictive cough (Shan-non et al., 1982, 2000). Indeed, the ventral res-piratory group may provide part of the outflow tomotoneurones involved in coughing since it isfound in close association with the nucleus am-biguus, the location of motoneurones innervatingthe upper and lower airway muscles (see above).Output of ‘cough’ NTS neurones may reach thenA via the raphe and/or other midline medullarynuclei as recent data demonstrate that discretelesions of this area abolish tracheobronchial andlaryngopharyngeal cough but not the aspirationreflex (Jakus et al., 1998). In addition, as well aswithin the NTS and nA, increased c-fos activityhas been demonstrated in neurones within themedial part of the lateral tegmental field and thelateral reticular nucleus during SLN evokedcoughing (Gestreau et al., 1997). The activation ofthe individual muscles could occur as a temporalsequence of individual reflex activations but sincecoughs are stereotyped within an individual (Kor-pas et al., 1996) it would seem more likely that aswith swallowing, there exists a pre-programmedmotor pattern which can be triggered by appro-priate stimuli. Shannon et al. (2000) argue againstthis, preferring a network model whereby the


same neurones are involved in generating respira-tory rhythm and during cough. This would beconsistent with earlier data indicating that duringcoughing, sneezing and aspiration reflexes firingof active neurones is altered and others recruited(Jakus et al., 1985) and that activity of pre-in-spiratory neurones is altered during both swallow-ing and vomiting (Zheng et al., 1997).

9. Conclusion

In summary, activity of airway muscles is aresult of both intrinsic and extrinsic mechanisms,the latter including excitatory parasympatheticand NANC innervations and inhibitory sympa-thetic and NANC innervations. The relative im-portance of the different controls varying betweenspecies. Parasympathetic activity is the most im-portant in setting the level of airway tone and isresponsible for most reflex changes. Inputs from avariety of sensory afferents and central nervousstructures interact to produce the final nervousoutput. Information from the central respiratorynetwork is particularly important in this respect.Although individual airway muscles are underseparate reflex controls, under certain circum-stances, e.g. swallowing and coughing, stereo-typed patterns of motor activity are generated bythe afferent input.

References

Barkmeier, J.M., Bielamowicz, S., Takeda, N., Ludlow, C.L.,2000. Modulation of laryngeal responses to superior laryn-geal nerve stimulation by volitional swallowing in awakehumans. J. Neurophysiol. 83, 1264–1272.

Barnes, P.J., 1997. Neuromodulation in airways. In: Barnes,P.J. (Ed.), Autonomic Control of the Respiratory System.Harwood Academic Publishers, The Netherlands, pp. 139–184.

Barnes, P.J., Chung, K.F., Page, C.P., 1998. Inflammatorymediators of asthma: an update. Pharmacol. Rev. 50,515–596.

Bellingham, M.C., Lipski, J., 1992. Morphology and electro-physiology of superior laryngeal nerve afferents and post-synaptic neurons in the medulla oblongata of the cat.Neuroscience 48, 205–216.

Berger, A.J., 1977. Dorsal respiratory group neurons in themedulla of cat: spinal projections, responses to lung infla-tion and superior laryngeal nerve stimulation. Brain Res.135, 231–254.

Black, J.L., 1997. Innervation of airway smooth muscle. In:Barnes, P.J. (Ed.), Autonomic Control of the RespiratorySystem. Harwood Academic Publishers, The Netherlands,pp. 185–200.

Bonham, A.C., Joad, J.P., 1991. Neurones in commissuralnucleus tractus solitarii required for full expression of thepulmonary C fibre reflex in rat. J. Physiol. Lond. 441,95–112.

Bonham, A.C., Coles, S.K, McCrimmon, D.R., 1993. Pul-monary stretch receptor afferents activate excitatory aminoacid receptors in the nucleus tractus solitarii in rats. J.Physiol. Lond. 464, 725–745.

Butcher, J.W, Paton, J.F.R., 1998. K+ channel blockade inthe NTS alters efficacy of two cardiorespiratory reflexes invivo. Am. J. Physiol. 274, R677–R685.

Coleridge, H.M., Coleridge, J.C.G., Schultz, H.D., 1989. Af-ferent pathways involved in reflex regulation of airwaysmooth muscle. Pharmacol. Therap. 42, 1–63.

Coleridge, H.M., Coleridge, J.C.G., Jordan, D., 1991. Integra-tion of ventilatory and cardiovascular control systems. In:Crystal, R.G., West, J.B. (Eds.), The Lung. ScientificFoundations, Raven Press, New York, pp. 1405–1418.

Davies, R.O., Kubin, L., Pack, A.I., 1987. Pulmonary stretchreceptor relay neurones of the cat: location and contralat-eral medullary projections. J. Physiol. Lond. 383, 571–585.

Dawid-Milner, M.S., Silva-Carvalho, L., Goldsmith, G.E.,Spyer, K.M., 1995. Hypothalamic modulation of laryngealreflexes in the anaesthetized cat: role of the nucleus tractussolitarii. J. Physiol. Lond. 487, 739–749.

Ezure, K., Otake, K., Lipski, J., She, R.B., 1991. Efferentprojections of pulmonary rapidly adapting receptor relayneurons in the cat. Brain Res. 564, 268–278.

Ezure, K., Tanaka, I., 1996. Pump neurons of the nucleus ofthe solitary tract project widely to the medulla. Neurosci.Lett. 215, 123–126.

Ezure, K., Tanaka, I., Miyazaki, M., 1998. Pontine projectionsof pulmonary slowly adapting receptor relay neurons in thecat. Neuroreport 9, 411–414.

Ezure, K., Tanaka, I., Miyazaki, M., 1999. Electrophysiologi-cal and pharmacological analysis of synaptic inputs topulmonary rapidly adapting receptor relay neurons in therat. Exp. Brain Res. 128, 471–480.

Ezure, K., Tanaka, I., 2000. Lung inflation inhibits rapidlyadapting receptor relay neuons in the rat. Neuroreport 11,1709–1712.

Ford, T.W., Bennett, J.A., Kidd, C., McWilliam, P.N., 1990.Neurones in the dorsal motor vagal nucleus of the cat withnon-myelinated axons projecting to the heart and lungs.Exp. Physiol. 75, 459–473.

Fox, A., 1996. Modulation of cough and airway sensory fibres.Pulm. Pharmacol. 9, 335–342.

Fryer, A.D., 1997. The cholinergic control of the airways. In:Barnes, P.J. (Ed.), Autonomic Control of the Respiratory


System. Harwood Academic Publishers, The Netherlands,pp. 59–86.

Gestreau, C., Bianchi, A.L., Grelot, L., 1997. Differentialbrainstem-fos-like immunoreactivity after laryngeal-in-duced coughing and its reduction by codeine. J. Neurosci.17, 9340–9352.

Gilbey, M.P., Jordan, D., Richter, D.W., Spyer, K.M., 1984.Synaptic mechanisms involved in the inspiratory modula-tion of vagal cardio-inhibitory neurones in the cat. J.Physiol. Lond. 356, 65–78.

Haxhiu, M.A., Deal, E.C., Jr., Cherniack, N.S., 1989. Influ-ence of respiratory drive on airway responses to excitationof lung C-fibres. J. Appl. Physiol. 67, 203–209.

Hines, T., Toney, G.M., Mifflin, S.W., 1994. Responses ofneurons in the nucleus tractus solitarius to stimulation ofheart and lung receptors in the rat. Cir. Res. 74, 1189–1196.

Jakus, J., Tomori, Z., Stransky, A., 1985. Activity of bulbarrespiratory neurones during cough and other respiratorytract reflexes in cats. Physiol. Bohemoslov. 34, 127–136.

Jakus, J., Stransky, A., Poliacek, I., Barani, H., Bosel’ova, L.,1998. Effects of medullary midline lesions on cough andother airway reflexes in anaesthetized cats. Physiol. Res.47, 203–213.

Jean, A., 1990. Brainstem control of swallowing: localizationand organization of the central pattern generator for swal-lowing. In: Taylor, A. (Ed.), Neurophysiology of the Jawsand Teeth. MacMillan Press, New York, pp. 294–321.

Jean, A., Kessler, J-P., Tell, F., 1993. Nucleus tractus solitariiand deglutition: monoamines, excitatory amino acids, andcellular properties. In: Barraco, I.R.A. (Ed.), Nucleus ofthe Solitary Tract. CRC Press, Boca Raton, pp. 361–375.

Jeggo, R.D., Wang, Y., Jordan, D., Ramage, A.G., 2000. Therole of the 5-HT3 receptors in the cardiopulmonary affer-ent-evoked response of NTS neurones in the anaesthetizedrat. J. Physiol. Lond. 523, 258–259.

Jewett, D.L., 1964. Activity of single efferent fibres in thecervical vagus nerve of the dog, with special reference topossible cardio-inhibitory fibres. J. Physiol. Lond. 175,321–357.

Jones, J.F.X., Jordan, D., 1993. Pulmonary C-fibre activationof brainstem respiratory neurones and vagal motoneuronesin anaesthetized cats and rats. Clin. Autonom. Res. 3, 75.

Jones, J.F.X., Wang, Y., Jordan, D., 1998. Activity of C fibrecardiac vagal efferents in anaesthetized cats and rats. J.Physiol. Lond. 507, 869–880.

Jordan, D., Spyer, K.M., 1986. Brainstem integration of car-diovascular and pulmonary afferent activity. Prog. BrainRes. 67, 295–314.

Jordan, D., Spyer, K.M., Withington-Wray, D.J., Wood,L.M., 1986. Histochemical and electrophysiolgical identifi-cation of cardiac and pulmonary vagal preganglionic neu-rones in the cat. J. Physiol. Lond. 372, 87P.

Jordan, D., 1996. Central nervous mechanisms in cough.Pulm. Pharmacol. 9, 389–392.

Jordan, D., 1997. Central nervous control of the airways. In:Jordan, D. (Ed.), Central Nervous Control of Autonomic

Function. Harwood Academic Publishers, Chur, pp. 63–107.

Karlsson, J.-A., 1996. The role of capsaicin-sensitive C-fibreafferent nerves in the cough reflex. Pulm. Pharmacol. 9,315–321.

Korpas, J., Sadlonova, J., Vrabec, M., 1996. Analysis of thecough sound: an overview. Pulm. Pharmacol. 9, 261–268.

Kubin, L., Davies, R.O., 1988. Sites of termination and relayof pulmonary rapidly adapting receptors as studied byspike-triggered averaging. Brain Res. 443, 215–221.

Laitinen, L.A., Laitinen, A., 1997. Innervation of the airways.In: Barnes, P.J. (Ed.), Autonomic Control of the Respira-tory System. Harwood Academic Publishers, The Nether-lands, pp. 1–19.

Leff, A.R., 2000. Role of leukotrienes in bronchial hyperre-sponsiveness and cellular responses in airways. Am. J.Respir. Crit. Care Med. 61, S125–S132.

Lipski, J., Ezure, K., Wong She, R.B., 1991. Identification ofneurons receiving input from pulmonary rapidly adaptingreceptors in the cat. J. Physiol. Lond. 443, 55–77.

Martin, R.E., Murray, G.M., Kemppainen, P., Masuda, Y.,Sessle, B.J., 1997. Functional properties of neurons in theprimate tongue primary mortor cortex during swallowing.J. Neurophysiol. 78, 1516–1530.

Martin, R.E., Kemppainen, P., Masuda, Y., Yao, D., Murray,G.M., Sessle, B.J., 1999. Features of cortically evokedswallowing in the awake primate (Macaca fascicularis). J.Neurophysiol. 82, 1529–1541.

McAllen, R.M., Spyer, K.M., 1978. Two types of vagal pre-ganglionic motoneurones projecting to the heart and lungs.J. Physiol. Lond. 282, 353–364.

McCallister, L.W., Connelly, J.C., Kaufman, M.P., 1988.Stimulation of H fields of Forel decreases total lung resis-tance in dogs. J. Appl. Physiol. 65, 2156–2163.

Mifflin, S.W., 1993. Laryngeal afferent inputs to the nucleus ofthe solitary tract. Am. J. Physiol. 269, R269–R276.

Mifflin, S.W., 1996. Convergent carotid sinus nerve and supe-rior laryngeal nerve afferent inputs to neurons in the NTS.Am. J. Physiol. 271, R870–R880.

Mitchell, R.A., Herbert, D.A., Baker, D.G., 1985. Inspiratoryrhythm in airway smooth muscle tone. J. Appl. Physiol. 58,911–920.

Mitchell, R.A., Herbert, D.A., Richardson, C.A., 1989. Neu-rohumoral regulation of airway smooth muscle: role of thetracheal ganglia. In: Lahiri, S., Forster, R.E., Davies,R.O., Pack, A.I. (Eds.), Chemoreceptors and Reflexes inBreathing. Oxford University Press, New York, pp. 299–309.

Miyazaki, M., Arata, A., Tanaka, I., Ezure, K., 1998. Activityof rat pump neurons is modulated with central respiratoryrhythm. Neuroci. Letts. 249, 61–64.

Mrini, A., Jean, A., 1995. Synaptic organization of the intersti-tial subdivision of the nucleus tractus solitarii and itslaryngeal afferents in the rat. J. Comp. Neurol. 355, 221–236.

Mutoh, T., Joad, J.P., Bonham, A.C., 2000. Chronic passivecigarette smoke exposure augments bronchopulmnary C-


fibre inputs to nucleus tractus solitarii neurones and reflexoutput in young guinea-pigs. J. Physiol. Lond. 523, 223–233.

Nishino, T., Tagaito, Y., Isono, S., 1996. Cough and otherreflexes on irritation of airway mucosa in man. Pulm.Pharmacol. 9, 285–292.

Nolan, P., 1998. Reflex responses to upper airway negativepressure and their role in obstructive apnoea. J. Physiol.Lond. 513P, 6S.

Paton, J.F.R., Li, Y.W., Kasparov, S., 1999. Reflex responseand convergence of pharyngoesophageal and peripheralchemoreceptors in the nucleus of the solitary tract. Neuro-science 93, 143–154.

Richardson, C.A., 1988. Power spectra of inspiratory nerveactivity with lung inflations in cats. J. Appl. Physiol. 64,1709–1720.

Richter, D.W., Spyer, K.M., 1990. Cardiorespiratory control.In: Loewy, A.D., Spyer, K.M. (Eds.), Central Regulationof Autonomic Functions. Oxford University Press, NewYork, pp. 189–207.

Rogers, D.C., 1997. Neural control of airway secretions. In:Barnes, P.J. (Ed.), Autonomic Control of the RespiratorySystem. Harwood Academic Publishers, The Netherlands,pp. 201–227.

Sant’Ambrogio, G., Sant’Ambrogio, F.B., 1996. Role of laryn-geal afferents in cough. Pulm. Pharmacol. 9, 309–314.

Sessle, B.J., 1973a. Excitatory and inhibitory inputs to singleneurones in the solitary tract nucleus and adjacent reticularformation. Brain Res. 53, 319–331.

Sessle, B.J., 1973b. Presynaptic excitability changes induced insingle laryngeal primary afferent fibres. Brain Res. 53,333–342.

Sevoz-Couche, C., Wang, Y., Ramage, A.G., Spyer, K.M.,Jordan, D., 2000. In vivo modulation of nucleus tractussolitarius (NTS) neurones by activation of 5-hydrox-ytryptamine receptors in rats. Neuropharmacology 39,2006–2016.

Shannon, R., Morris, K.F., Lindsey, B.B., 1982. Nucleustractus solitarius responses during fictive cough. Fed. Proc.9, A667.

Shannon, R., Baekey, D.M., Morris, K.F., Li, Z., Lindsey,B.G., 2000. Functional connectivity among ventrolateralmedullary respiratory neurones and responses duringfictive cough in the cat. J. Physiol. Lond. 525, 207–224.

Silva-Carvalho, L., Paton, J.F.R., Rocha, I., Goldsmith, G.E.,Spyer, K.M., 1998. Convergence properties of solitary tract

neurons responsive to cardiac receptor stimulation in theanaesthetized cat. J. Neurophysiol. 79, 2374–2382.

Smart, S.J., Casale, T.B., 1997. Abnormal autonomic controlin respiratory disease. In: Barnes, P.J. (Ed.), AutonomicControl of the Respiratory System. Harwood AcademicPublishers, The Netherlands, pp. 313–338.

St. John, W.M., 1990. Neurogenesis, control, and functionalsignificance of gasping. J. Appl. Physiol. 68, 1305–1315.

Tanaka, Y., Yoshida, Y., Hirano, M., 1995. Expression ofFos-protein activated by tactile stimulation on the laryn-geal vestibulum in the cat’s lower brain stem. J. Laryngol.Otol. 109, 39–44.

Taylor, E.W., Jordan, D., Coote, J.H., 1999. Central controlof the cardiovascular and respiratory systems and theirinteractions in vertebrates. Physiol. Rev. 79, 855–916.

Umezaki, T., Matsuse, T., Shin, T., 1998. Medullary swallow-ing-related neurons in the anaesthetized cat. Neuroreport9, 1793–1798.

Undem, B.J., Myers, A.C., 1997. Autonomic ganglia. In:Barnes, P.J. (Ed.), Autonomic Control of the RespiratorySystem. Harwood Academic Publishers, The Netherlands,pp. 87–118.

von Euler, C., 1997. Neural organization and rhythm genera-tion. In: Crystal, R.G., West, J.B. (Eds.), The Lung, 2nd.Lippincott-Raven Publishers, Philadelphia, pp. 1711–1724.

Widdicombe, J.G., 1961. Action potentials in vagal efferentnerve fibres to the lungs of the cat. Naunyn-Schmied.Arch. Exp. Path. Pharmacol. 241, 415–432.

Widdicombe, J.G., 1966. Action potentials in parasympatheticand sympathetic efferent fibres to the trachea and lungs ofdogs and cats. J. Physiol. Lond. 186, 56–88.

Wilson, C.G., Zhang, Z., Bonham, A.C., 1996. Non-NMDAreceptors transmit cardiopulmonary C-fibre input in nu-cleus tractus solitarii in rats. J. Physiol. Lond. 496, 773–785.

Windhorst, U., 1996. Spinal cord and brainstem: patterngenerators and reflexes. In: Greger, R., Windhorst, G.(Eds.), Comprehensive Human Physiology. Springer-Ver-lag, Heidelberg, pp. 1007–1032.

Withington-Wray, D.J., Mifflin, S.W., Spyer, K.M., 1988.Intracellular analysis of respiratory-modulated hypoglossalmotoneurons in the cat. Neuroscience 25, 1041–1051.

Zheng, Y., Umezaki, T., Nakazawa, K., Miller, A.D., 1997.Role of pre-inspiratory neurons in vestibular and laryngealreflexes and in swallowing and vomiting. Neurosci. Lett.225, 161–164.

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