modulation of sensory nerve function in the airways

Pulmonary Pharmacology & Therapeutics (1998) 11, 319–330Article No. pu990160

PULMONARYPHARMACOLOGY& THERAPEUTICS

Modulation of Sensory Nerve Function in the Airways

D. Spina

The Sackler Institute of Pulmonary Pharmacology, Department of Respiratory Medicine and Allergy,GKT School of Medicine, King’s College London, Bessemer Rd, London SE5 9PJ, UK

INTRODUCTION bronchial hyperreactivity may not be a useful clinicalindicator of asthma severity and/or may be unrelated

A striking characteristic of asthma is a heightened to the presence of eosinophils. Alternatively, the lacksensitivity of asthmatics to a range of stimuli that of correlation between these variables may be a con-ordinarily are without effect in normal subjects. The sequence of using an inappropriate spasmogen, whichterm bronchial hyperresponsiveness has been coined, may underestimate the degree of airways hyper-and describes the increased sensitivity (PC20; defined responsiveness present. This view is constant with theas a lowering of the provocative concentration that recent finding that the number of eosinophils detectedproduces a 20% fall in forced expiratory volume in in sputum, BAL and bronchial biopsies was more1 s and reactivity (defined as an increase in the slope closely related to airways responsiveness to bradykininand/or loss in the plateau of the dose response curve) than methacholine.7,8 This difference may be indicativeof the airways to inhaled bronchoconstrictor agonists. of the mechanism by which bradykinin induces bron-It has been suggested that different mechanisms may choconstriction, secondary to the activation of afferentaccount for the changes in sensitivity and reactivity of nerves. An increase in sensory nerve activity may bethe airways to bronchoconstrictor agonists, including a common pathway by which various stimuli induceairway smooth muscle hyperplasia, facilitated ex- bronchoconstriction of the airways and hence, maycitation of smooth muscle cells, loss of homeostatic contribute toward the bronchial hyperresponsivenessbronchodilator mechanisms, loss of epithelial integrity seen in mild to moderate asthmatic subjects. In thisand reduction of luminal diameter secondary to in- regard, it has recently been shown that eosinophil-creased volume of airway smooth muscle and mucosal derived products and activated eosinophils induce theoedema.1 It is of interest that the term non-selective release of substance P from rat sensory neurones.9

bronchial hyperresponsiveness has been used to dis- Thus, inflammatory cells may increase the activity oftinguish asthmatics from healthy individuals, when it afferent nerves, which could be one mechanism thatis quite clear that this is not the case. Indeed, asth- leads to heightened airways responsiveness to ‘in-matics often demonstrate a ‘selective’ bronchial hyper- directly’ acting stimuli such as exercise, fog, cold airresponsiveness to a number of stimuli including and chemical irritants, which are known to elicitbradykinin, distilled water, cold air, exercise, ad- an exacerbation of asthma in the environment ofenosine, sulphur dioxide and sodium metabisulphite, susceptible individuals.and lack of correlation between PC20 estimates fordifferent bronchoconstrictor agonists is relativelyfrequent.2 Furthermore, following antigen challenge CONTRIBUTION OF AIRWAY SENSORYof asthmatic subjects, the increase in airways re- NERVES TO BRONCHIALsponsiveness to bradykinin is far greater and more HYPERRESPONSIVENESSprotracted than methacholine.3 Since bradykinin in-duces reflex bronchoconstriction, one interpretation Human airways are innervated by populations ofof this study is that afferent nerve activity can be afferent nerves including myelinated Ad-and un-increased during inflammation. myelinated C-fibres. Stimulation of these sensory

While current dogma suggests that the influx of nerves result in reflex cough and bronchoconstric-inflammatory cells, notably eosinophils, is important tion,10 and it is this latter population of afferentin the pathogenesis of asthma, several studies have nerves that have received considerable attention infound a lack of correlation between bronchial hyper-

the context of bronchial hyperresponsiveness. It hasreactivity and asthma severity,4,5 and lung eos-

been claimed that substance P-containing nerves areinophilia.5–7 It has therefore been suggested that

more abundant in lungs obtained at autopsy fromE-mail: [email protected] asthmatics as compared with healthy individuals,11

1094–5539/98/050319+12 $30.00/0 1998 Academic Press319

320 D. Spina

although this observation has not been confirmed in dioxide (SO2),27,28 metabisulphite,29,30 distilled H2O(‘fog’),31 and adenosine,32 which are otherwise re-subsequent studies.12,13 Using high performance liquid

chromatography, a reduction in substance P-like im- fractory in healthy subjects. While degranulation ofmast cells has often been cited as a mechanism tomunoreactivity was observed in the lungs of in-

dividuals who died of asthma or who were undergoing account for bronchoconstriction to a number of thesestimuli, there is a significant body of evidence thatthoracotomy, compared with age-matched non-dis-

eased subjects.14 Similarly, there appears to be a loss implicates an involvement of sensory nerves in thisresponse. The recording of action potentials fromof substance P- and calcitonin gene related peptide

(CGRP)-like immunoreactivity in sensory nerves single vagal afferents originating from the airwaysprovides a direct measure of afferent activity andfound in synovial tissue in patients with rheumatoid

arthritis.15 The reduction in neuropeptide content in substances which stimulate mucosal sensory receptors,either directly, or indirectly following mechanicalthe asthmatic lung may be an indication of loss of

neuropeptide from sensory nerves during chronic in- changes in the airways (smooth muscle constriction,mucosal oedema and submucosal gland secretion)flammation.

This circumstantial evidence implicating release of would be expected to stimulate action potentials inafferent nerves (Table 1). Furthermore, antigen pro-sensory neuropeptides in asthma is consistent with

the detection of substance P-like immunoreactivity in vocation in allergic rabbits,33 and guinea-pigs,34 canalso lead to the activation of afferent nerves. Similarly,bronchoalveolar lavage fluid in atopic asthmatics as

compared with healthy individuals.16 Furthermore, the release of neuropeptides from rodent airwayshas been documented for sodium metabisulphite,35concentrations of substance P-like immunoreactivity

in bronchoalveolar lavage was further increased in bradykinin and capsaicin (Table 1).36 Together, thesestudies highlight the point that reflex broncho-atopic asthmatics who had experienced an acute re-

action to inhaled allergen;16 elevated levels of sub- constriction can be elicited by a number of stimuliwhich are known to activate afferent nerves. Thus, anstance P-like immunoreactivity have also been

detected in the sputum of patients with asthma or increase in sensory nerve function would be expectedto enhance airways responsiveness to these agentschronic bronchitis patients, as compared with healthy

individuals following hypertonic saline inhalation.17 following an inflammatory insult.Capsaicin is often employed as a selective stimulantSimilarly, individuals with idiopathic cough who have

increased sensitivity to capsaicin have increased levels of C-fibres in experimental studies, although, it isclear that it can stimulate rapidly adapting receptorsof neuronal CGRP and, to a lesser extent, substance

P-immunoreactivity in bronchial biopsies than healthy (RARs), albeit to a lesser extent than C-fibres. It mightbe anticipated that asthmatics would be extremelysubjects.18 The human data provides a snap-shot of

neuropeptide synthesis, transport to contral/peri- sensitive to the bronchoconstriction induced by cap-saicin. However, no substantial difference in airwayspheral terminals and release, which would explain the

differences reported for neuropeptide levels in these responsiveness to inhaled capsaicin was observed be-tween asthmatic and healthy individuals.37 A possiblestudies. This complexity is highlighted by experimental

data showing that neuropeptide levels in the lung can explanation for this anomaly is the finding that cap-saicin causes bronchodilation in asthmatics.38 In-decrease following acute challenge with toluene di-

isocyanate (TDI),19 or increase following repeated terestingly, in subjects in whom heart-transplants weremade and where afferent innervation may be com-challenge with antigen,20 while 24 h following acute

challenge with antigen there was an increase in neuro- promised,39 bronchodilation to capsaicin was still ob-served.40 This suggests that capsaicin may eitherpeptide content in the trachea.21 These studies show

that neuropeptide levels can undergo marked changes activate a local inhibitory reflex or alternatively, maycause bronchodilation directly. Indeed, capsaicin hasdepending on the inflammatory stimulus and exposure

period. been shown to induce relaxation of human bronchialsmooth muscle in vitro that is independent of theOther studies have documented possible changes

in neurokinin receptor expression in asthmatics. An activation of sensory nerves,41,42 and may confoundany attempt to document an increase in bronchialincrease in mRNA transcripts for neurokinin-1,22 and

neurokinin-2,23 receptors was demonstrated in lung responsiveness to capsaicin in asthmatics.One possible mechanism to account for the ‘se-tissue from asthmatic compared with non-asthmatic

subjects. This may be in response to local release of lective’ bronchial hyperresponsiveness to a number ofthe stimuli mentioned earlier might be an increase inneuropeptides and consequent neuropeptide mRNA

in sensory nerves and/or an increase in afferent activity afferent activity. Inflammatory mediators includingprostaglandins, neuropeptides, cytokines and growthawaits documentation in man.

There is considerable clinical evidence dem- factors sensitize afferent nerves leading to hyperalgesiain the skin and it has been proposed that a similaronstrating that asthmatics bronchoconstrict to a num-

ber of stimuli including bradykinin,24–26 sulphur mechanism may operate in the airways resulting in

Modulation of Sensory Nerve Function in the Airways 321

Table 1 A summary of animal studies which provides evidence that a number of stimuli known to induce bronchoconstriction inasthmatic subjects can activate afferent nerves as assessed from measurement of action potential generation and neuropeptide releasefrom sensory nerves.

Afferent activity Neuropeptide release

Stimulant In vitro studies In vitro studies In vitro studiesRARs C-fibres

Sulphur dioxide, sodium Guinea-pigb126 Cat127 Dog129 Guinea-pig35,130,131

metabisulphite, low pH Rabbit128 Rat100

Adenosinec Rat132 Guinea-pig133

Distilled water Guinea-piga b61 Dog134 Dog134

Bradykinin Guinea-pigb135 Dog136 Dog136 Guinea-pig36

Guinea-pig137 Guinea-pig137

Neuropeptides Rabbit138,139 Rabbit138

Capsaicin Guinea-piga b34,135 Cat140,141 Cat55,57,141 Guinea-pig36

Guinea-pig76,137 Dog142 Rat100

Guinea-pig137

Stimulation of Ad (a) and/or C (b) fibres.c Adenosine stimulates C-fibres via A1-receptors in the rat and inhibits substance P release via A2-receptors in guinea-pig lung.

bronchial hyperresponsiveness (Fig. 1).43 This hypo- actions are likely to have resolved. However, somethesis is supported by studies which have investigated caution is warranted if capsaicin alone is relied uponthe effect of chemically impairing sensory nerve func- to implicate a role for sensory nerves in mediatingtion on bronchial hyperresponsiveness induced by bronchial hyperresponsiveness. In this context, thereallergic and non-allergic stimuli (Table 2). Capsaicin, is considerable evidence demonstrating the ability ofthe principle pungent from peppers, is a selective neurokinin receptor antagonists in attenuating bron-stimulant of sensory nerves and a variety of functional, chial hyperresponsiveness to a number of the stimulibiochemical and electrophysiological studies have elu- discussed thus far (Table 1).51,52 Chronic treatmentcidated the mechanism by which capsaicin activates with capsaicin generally leads to a suppression ofsensory nerves. Capsaicin stimulates a receptor which bronchial hyperresponsiveness, however, in some cir-is a non-selective cation channel that has recently cumstances, bronchial hyperresponsiveness can bebeen cloned and expressed in non-neuronal cells.44 augmented following chronic treatment with cap-Stimulation of the vanilloid receptor leads to mem- saicin, and indicates that sensory nerves may play abrane depolarization, calcium entry into neuronal cells protective role in mucosal defence against en-and release of neuropeptides. Chronic treatment with vironmental irritants in some species (Table 2). Whilecapsaicin leads to the depletion of sensory neuro- such studies are difficult to perform in asthmaticpeptides and/or destruction of C-fibres and therefore, subjects, it is of interest that chronic treatment withhas often been employed to study the role of sensory capsaicin appeared to reduce vascular reactivity in theneuropeptides in various biological processes.45 Fol- upper respiratory tract of subjects with non-allergiclowing chronic treatment with capsaicin, a substantial rhinitis,53 suggesting that sensory neuropeptides areloss of substance P and CGRP immunoreactivity is involved in the increased responsiveness of the upperevident in the lung, that is associated with diminished respiratory tract.bronchoconstrictor response and reduced plasma pro-tein extravazation by vagal stimulation or cap-saicin.45,46

Whilst chronic treatment with capsaicin may beMODULATION OF SENSORY NERVEconsidered to have a singular action, it should beACTIVITYnoted that a number of studies have revealed that

capsaicin has other effects, including antagonism ofA number of drugs, some of which are currently usednicotine receptor channels;47 inhibition of platelet ag-in the treatment of asthma, attenuate acute bronchialgregation in vitro,48 inhibition of lipid peroxidationhyperresponsiveness to a variety of indirectly actingof membranes by various irritants,49 inhibition of NF-bronchoconstrictor agonists that may be a con-j B;50 and destruction of some Ad fibres.10 It is unclearsequence of suppression of afferent activity and/orto what extent these actions contribute, if any, to theinhibition of neuropeptide release. Novel agents whicheffect of capsaicin treatment on bronchial hyper-target sensory nerves may offer new therapeutic av-responsiveness in vivo, as the physiological ex-enues for the suppression of bronchial hyper-periments are performed at least 3–7 days following

capsaicin treatment, when many of these unwanted responsiveness (Fig. 1).

322 D. Spina

Sensitizers• bradykinin• prostaglandins• PAF• 15 HPETE

• nitric oxide• IL-1β• NGF

Spasmogens/tussive agents• bradykinin• SO2• metabisulphite

• adenosine• distilled water• capsaicin

Inhibitors: 'afferent function'• nedocromil• K+ channel openers• moguisteine• frusemide

Inhibitors: 'efferent function'• β2-agonists• nedocromil• cromoglycate• theophylline• nociceptin• µ-opioid agonists• K+ channel openers• PDE4 inhibitors• frusemide• α2-agonists

Sites of action• epithelium• mucus glands• blood vessels• nerves• endothelium• airway smooth muscle

• eosinophils• monocytes• T lymphocytes• B lymphocytes• fibroblasts

substance P, NKA, CGRP

CNS

ReflexCough

ReflexBronchoconstriction

Vagus nerve

Nodose ganglion

Jugular ganglion

Ca+2

K+

Fig. 1 Diagrammatic representation of the contribution of sensory nerves to bronchial hyperresponsiveness. Inflammatory mediators(sensitizers) can increase sensory nerve function in the skin leading to hyperalgesia and a number of these mediators can also inducebronchial hyperresponsiveness in the airways. Stimulation of sensory nerves results in the release of proinflammatory neuropeptides,reflex cough and bronchoconstriction. A number of pharmacological agents have been shown to inhibit the release of sensoryneuropeptides (‘efferent function’) and/or inhibit excitation of afferent nerves (‘afferent function’). The development of drugs that canreduce sensory nerve function may be useful for the suppression of bronchial hyperresponsiveness. IL-1b, interleukin 1b; NGF, nervegrowth factor; NKA, neurokinin A; CGRP, calcitonin gene-related peptide; PDE, phosphodiesterase; CNS, central nervous system.

Suppression of afferent activity the presence of either low chloride solutions or chlor-ide channel blockers, implicating a role for chloridechannels.58 Thus, prolonged treatment with anti-Antiallergic drugsallergic drugs could induce a refractory state in sensorynerves which would suppress afferent activity to sub-Disodium cromoglycate (DSCG) has been shown to

reduce afferent activity from C-fibres,54 but not rapidly stances which stimulate these nerves. Mild asthmaticsderive some benefit from the chronic use of theseadapting receptors in the dog.55 Nedocromil is effective

against cough induced by citric acid inhalation,56 and drugs,59 but clearly there is scope for improvementand it remains to be established whether drugs withit would appear that nedocromil initially activates,

then blocks bronchial C-fibre activity in the dog, greater potency in modulating chloride channelfunction on nerves will be useful in the suppressionwithout affecting either pulmonary C-fibre or rapidly

adapting receptor activity.57 Nedocromil but not of bronchial hyperresponsiveness.DSCG caused depolarization of rabbit vagus nervethat was followed by a refractory period where the

Frusemidevagus was unresponsive to the drug, although thenerve type from which the recording was made was The loop diuretic frusemide inhibits the Na+/K+/2Cl−

cotransporter in the epithelium of renal tubules andnot specific.58 The role of ion channels in this responsewas further investigated and it was found that nedo- attenuates bronchoconstriction to a number of in-

directly acting stimuli,60 and it has been reported thatcromil-induced nerve depolarization was inhibited in


Table 2 Representative studies demonstrating the effect of chronic treatment with capsaicin on airways hyperresponsiveness induced byallergic and non-allergic stimuli.

Stimuli Spasmogen Effect of capsaicin

Antigen Acetylcholine, histamine 5-hydroxytryptamine Inhibited143–145

Augmented146

TDI Methacholine, acetylcholine Inhibited147,148

Cold air Not determinedLPS Histamine Inhibited149

Ozone Histamine Inhibited150,151

Methacholine Augmented152

Citric acid Acetycholine Inhibited153

Parainfluenza-3 Acetylcholine Inhibited154

Cigarette smoke Acetylcholine, histamine Inhibited155,156

PAF Histamine Inhibited157,158

15-HPETE Histamine Inhibited159

Poly-L-lysine Methacholine Inhibited160

Neuropeptides Not determined

frusemide inhibits the excitation of Ad fibres to low agents can cause bronchoconstriction and would bechloride (isotonic glucose) but not to distilled water likely to inhibit the defensive cough reflex.67

or hypertonic saline. Furthermore, frusemide waswithout effect on the excitation of C-fibres to capsaicinin guinea-pig ioslated vagal afferents, and suggest that

Potassium channel openersfrusemide may have actions other than inhibition ofafferent activity.61 The effect of this drug on the activity The targeting of ion channels found on afferent nerves,of sensitized afferent nerves remains to be established. including potassium channels, may provide a novel

therapeutic approach in the suppression of bronchialhyperresponsiveness.68 Potassium channel openersAnalgesicsevoke the efflux of potassium from these channels

The l-opioid analgesic, codiene and BW443C, a novel leading to hypolarization of cells. The ATP-sensitivepolar peptide which activates l-opioid receptors, at- potassium channel opener, YM394, attenuates PAF-tenuated capsaicin-induced bronchoconstriction in the induced bronchial hyperresponsiveness in guinea-guinea-pig.62 Furthermore, BW443C attenuated im- pigs,69 and other potassium channel openers have alsopulses generated either spontaneously (Ad, C-fibres) been documented to attenuate bronchial hyper-or following stimulation with histamine (Ad) and responsiveness following stimulation of immune-com-capsaicin (C) from vagal aggerents originating from plex,70 independent of bronchodilation, and mightthe lung.43 BW443C was without significant action on involve an action on sensory nerves. The calciumbaseline hyperresponsiveness to histamine in mild

activated potassium Ca(K) channel opener, NS1619,stable asthmatics who were taking inhaled beclo-

inhibited the excitation of Ad and C-fibres to distilledmethasone.63 It remains to be established whether

water and bradykinin, respectively,71 and has sub-metabolism by endopeptidase in the epithelium or

sequently been demonstrated to attenuate cough in-dose limitation due to irritant activity, may accountduced by citric acid,71 although the effect of thisfor negative clinical result. The selection of a patientsubstance on bronchial hyperresponsiveness remainspopulation not taking glucocorticosteroid medicationto be established.would be more appropriate to test the effectiveness

of novel therapeutic agents.

c-aminobutyric acid (GABA)Local anaesthetics

Recent studies have documented the presence of GA-Local anaesthetics are commonly used to preventBAB receptors in the lung and activation of thesereflex-induced bronchoconstriction from mechanicalreceptors bu the GABAB-selective agonist, baclofen,irritation during bronchoscopy. Intravenous or aero-inhibits bronchospasm and cough via an inhibitorysol administration of lignocaine reduced airways re-action on parasympathetic and sensory nerves.72 Sim-sponsiveness to histamine,64,65 and hypertonicilarly, baclofen has also been reported to attenuatesaline,64 but was ineffective against distilled water-cough induced by capsaicin in healthy subjects,73 andinduced bronchoconstriction,66 in asthmatics. The pos-bronchial hyperresponsiveness in subjects with cer-sibility of suppressing bronchial hyperresponsiveness

with local anaesthetics may be limited since these vical spinal cord injury.74

324 D. Spina

Others neuropeptide Y,90 and galanin,91 have all been shownto inhibit the eNANC response in guinea-pig isolated

Moguisteine ((R)(S)-2-(2-methoxyphenoxy)-methyl-airways.

3-ethoxycarbonyl-acetyl-1)(3-thiazolidine) is a novelRecently, screening of cDNA library for novel

non-narcotic, antiinflammatory agent that inhibitsopioid receptors revealed sequences for a receptor

bronchial hyperresponsiveness to PAF and cigarette(ORL) with low affinity for opioids and was identified

smoke in guinea-pigs;75 stimuli which have been shownin murine and human brain.92 The endogenous ligandto induced hyperresponsiveness via a sensory nerve-for this receptor was also found,93,94 and coined noci-dependent pathway (Table 2). Furthermore, impulseceptin because of its hyperalgesic properties in vivo.discharges evoked by capsaicin from rapidly adaptingHowever, a number of studies have since been pub-receptors in the guinea-pig,76 and dog,77 is inhibited bylished which support the view that nociceptin hasmoguisteine. The vagal reflex induced by aerosolizedanalgesic properties by modulating neuronal functioncapsaicin in the guinea-pig was inhibited by the 5-both centrally and peripherally.95 Recently, we dem-HT1B/1D receptor agonist, sumatriptan and the 5-HT3 onstrated that nociceptin attenuated the release ofreceptor antagonist, granisetron,78 and suggests novelsubstance P from guinea-pig airways;96 consistent withalternatives for the suppression of vagal afferents.the detection of nociceptin-positive fibres in guinea-pigbronchi.97 While the effect of nociceptin on bronchial

Neuropeptide release hyperresponsiveness and cough remain to be es-tablished, it has recently been shown that nociceptinInhibition of neuropeptide release offers another po-may alter afferent conduction in the periphery,98 sug-tential target for the suppression of afferent nervegesting that activation of the ORL receptor can mod-activity and a number of pharmacological substancesulate afferent activity by suppression neuronalcan inhibit neuropeptide release from airway tissue.67

conduction and/or neuropeptide release. It remainsto be established whether non-peptide agonists with

Antiallergic drugs selectivity for the ORL-receptor can be synthesizedand whether these substances can reduce cough andElectrical field stimulation (EFS) of non-adrenergic–bronchial hyperresponsiveness.non-cholinergic (eNANC) nerves in guinea-pig isol-

In contrast to the inhibitory effect of a number ofated bronchus results in the release of sensorystimuli against neuropeptide release from the airways,neuropeptides which induce contraction of airwaythereby demonstrating species differences. Thus, pro-smooth muscle. Nedocromil was more effective thanstacylin,99 and prostaglandins,100 appear to promoteDSCG in attenuating the EFS-induced contraction ofthe release of neuropeptides from guinea-pig andguinea-pig isolated bronchus, and was unrelated to alrat airways, respectively. Interestingly, clinical studiesalteration in airway smooth muscle function by thishave shown that PGE2,101 and prostacyclin,102 at-agent.79 Similarly, DSCG failed to inhibit the releasetenuates reflex bronchospasm triggered by meta-of substance P from rat trachea.80 Thus, it appearsbisulphite and distilled water respectively, in asthmaticthat nedecromil is more effective than DSCG at in-subjects. Since the protection afforded by PGE2 andhibiting the release of neuropeptides from airwayprostacyclin was unrelated to functional antagonismsensory nerves. However, both agents may have aof airway smooth muscle, this suggests that thesepreferential action by inhibiting the activation ofsubstances may attenuate afferent nerve activity inafferent nerves. Nedecromil has no effect on cholin-man.ergic neurotransmission in the guinea-pig,79 although

In vivo studies have also demonstrated that l-this drug attenuated the substance P induced fa-opioids,62,103 and baclofen,103 inhibited atropine re-cilitation of cholinergic neurotransmission in the rab-sistant vagal induced bronchospasm that was mostbit.81 It is unclear whether this effect is due tolikely due to an action on sensory nerves, since thesenedocromil behaving as a neuropeptide antagonist.substances failed to attenuate bronchoconstrictionDSCG displaces 125I-labelled substance P from humanto exogenously administered bronchoconstrictorskin,82 yet failed to inhibit neurokinin-1 receptor me-agonists.diated activation of human astrocytoma cells or con-

traction of guinea-pig isolated trachea.83 Similarly,nedocromil did not appear to antagonize substance P- Non-receptor-dependent mechanismsinduced contraction of guinea-pig isolated bronchus.79

The non-selective phosphodiesterase isoenzymeinhibitor, theophylline;85,104 the phosphodiesterase

Receptor-dependent mechanisms(PDE)4 isoenzyme inhibitors, rolipram and Ro-20-1724;105–107 the anti-allergic drug, ketotifen;108 the ad-The a2-adrenoceptor agonist, clonidine;84 the b2-ad-

renoceptor agonists, procaterol, salbutamol and efor- enylate cyclase stimulator, forskolin;85 the potassiumchannel openers cromakalim and pinacidil;109 the loopmoterol;85,86 prostaglandin E1,85 prostaglandin E2;87


diuretics, frusemide and bumetanide;110 and the phos- neuropeptide release has also been investigated andphatase 1/2A inhibitor, okadaic acid,111 have also been it has been suggested that calcium activated potassiumshown to inhibit the eNANC response in guinea-pig channels may be a common pathway by which mod-isolated airways. ulation of neuropeptide release is achieved following

In vivo studies have also demonstrated that the activation of a number of receptors located on pre-PDE4 inhibitor, CDP840,112 attenuated the atropine junctional terminals of sensory nerves in the air-resistant vagal induced bronchospasm that was un- ways.67,90 However, this mechanism may not be uni-related to a post-junctional mechanism of action. versal, as it has recently been shown that the calcium-Furthermore, PDE4 inhibitors can attenuate citric activated potassium channel blocker, iberiotoxin, didacid cough in allergic guinea-pigs following antigen not attenuate the ability of nociceptin to inhibit neuro-challenge, but not in naı̈ve animals,113 and indicates peptide release from the airways.97 Direct coupling,that drugs may be developed which specifically target or indirect modulation of voltage-dependent calciumsensory nerves with increased functionality. While a channels on sensory nerves to a number of the ne-number of studies have shown that PDE4 inhibitors uromodulators discussed above,121–124 may also facili-can abrogate bronchial hyperresponsiveness induced tate inhibition of neuropeptide release followingby PAF, ozone, antigen and LPS,114 it is of interest receptor activation in the airways, and targeting ofthat capsaicin can also abrogate bronchial hyper- calcium channels on activated sensory nerves may beresponsiveness to these same stimuli (Table 2). a novel therapeutic approach for the suppression ofWhether PDE4 inhibitors attenuate bronchial hyper- bronchial hyperresponsiveness.responsiveness via an inhibitory action on sensory While a number of studies have demonstrated thatnerves remains to be established, although this hypo- neuropeptide release can be modulated following elec-thesis is consistent with the inhibitory action of PDE4 trical induced depolarization of airway sensory nerves,inhibitors on sensory nerve function as outlined above a different picture emerges with capsaicin. A numberand of the localization of PDE4 immunoreactivity of studies have investigated the mechanisms whichto afferent nerves, albeit, olfactory neurones in the regulate the function of the vanilloid receptor, in-mouse.115 Moreover, PDE4 inhibitors also reduce the cluding the role of protein phosphatases,125 and it isrecruitment of eosinophils into the lung following of interest that galanin,91 l-opioids,89 nociceptin,96,97

aerosol challenge to the stimuli mentioned above,116PDE4 inhibitors,106,107 and okadaic acid,111 which have

and since activated eosinophils are known to stimulate been shown to modulate neuropeptide release fol-sensory nerves in culture,9 PDE4 inhibitors may in- lowing nerve depolarization, failed to attenuate thedirectly reduce sensory nerve activity secondary to contractile response elicited by capsaicin. In one study,inhibition of inflammatory cell recruitment and/or morphine was found to inhibit the release of neuro-activation in the airways. Clearly futher studies are kinin-1-like immunoreactivity by capsaicin via a na-required to confirm the presence of PDE4 in afferent loxone-independent mechanism.118 Since capsaicinnerves originating from the airways. stimulation can elicit neuropeptide release directly

It is possible that cyclic AMP-elevating drugs may (capsazepine sensitive vanilloid receptor/channel) andreduce eNANC responses by behaving as functional subsequent to nerve depolarization (x-conotoxin sens-antagonists at post-junctional smooth muscle sites, a itive calcium channel),45 it is clear that the lattercaveat that should be considered when interpreting the pathway is more amenable to modulation by a numberresults of these studies. However, cholinergic responses of pharmacological agents thus far investigated.were not attenuated by rolipram,105–107 or okadaicacid,111 and the contractile response to exogenouslyadministered neuropeptides were not significantly at-

CONCLUSIONtenuated by these agents at concentrations whichhad a preferential action on the contractile response

While the role for sensory nerves as contributorselicited following EFS. Together, these studies suggestto bronchial hyperresponsiveness in asthma is notthat in the guinea-pig, cyclic AMP-dependent mech-proven, it is a particularly attractive hypothesis sinceanisms lead to inhibition of neuropeptide release init offers the prospect of a common pathway for hyper-the airways. A number of studies have also in-responsiveness due to antigens and environmentalvestigated the effect of drugs on the release of neuro-pollutants. This provides an exciting opportunity topeptides directly. Thus, neuropeptide release fromdevelop novel substances which may suppress bron-airway sensory nerves is inhibited by isoprenaline,117 l-chial hyperresponsiveness via an action on sensoryopioids,80,118 theophylline,60 and nociceptin.96,97,119 Fur-nerves. Experimental data suggest that this may bethermore, the potassium channel opener lemakalimpossible, as a number of pharmaceutical agents whichinhibited neuropeptide release from sensory nerves incan modulate sensory nerve function appear to at-rat skin.120

The mechanism by which various drugs inhibit tenuate bronchial hyperresponsiveness and cough.

326 D. Spina

17. Tomaki M, Ichinose M, Miura M, Hirayama Y, YamauchiACKNOWLEDGEMENTSH, Nakajima N, Shirato K. Elevated substance P content ininduced sputum from patients with asthma and patientswith chronic bronchitis. Am J Respir Crit Care Med 1995;The author wishes to acknowledge support from Joint151: 613–617.Research Committee, King’s College School of Medi-

18. O’Connell F, Springall D R, Moradoghli-Haftvani A,cine and Dentistry. Krausz T, Price D, Fuller R W, Polak J M, Priden B.

Abnormal intraepithelial airways nerves in persistentunexplained cough? Am J Respir Crit Care Med 1995; 152:2068–2075.

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