An excessive, irritable, productive or non-productive coughing associated with airway inflammation belongs to pathological cough. Increased activation of airway vagal nociceptors in pathological conditions results from dysregulation of the neural pathway that controls cough. A variety of mediators associated with airway inflammation overstimulate these vagal airway fibers including C-fibers leading to hypersensitivity and hyperreactivity. Because current antitussives have limited efficacy and unwanted side effects there is a continual demand for the development of a novel more effective antitussives for a new efficacious and safe cough treatment. Therefore, inhibiting the activity of these vagal C-fibers represents a rational approach to the development of effective antitussive drugs. This may be achieved by blocking inflammatory mediator receptors or by blocking the generator potential associated with the specific ion channels. Because voltage-gated sodium channels (NaVs) are absolutely required for action potentials initiation and conduction irrespective of the stimulus, NaVs become a promising neural target. There is evidence that NaV1.7, 1.8 and 1.9 subtypes are predominantly expressed in airway cough-triggering nerves. The advantage of blocking these NaVs is suppressing C-fiber irrespective to stimuli, but the disadvantage is that by suppressing the nerves is may also block beneficial sensations and neuronal reflex behavior. The concept is that new antitussive drugs would have the benefit of targeting peripheral airway nociceptors without inhibiting the protective cough reflex.

Department of Pathophysiology Jessenius Faculty of Medicine Comenius University Martin Slovakia

Zobrazit více v PubMed

ADCOCK JJ, DOUGLAS GJ, GARABETTE M, GASCOIGNE M, BEATCH G, WALKER M, PAGE CP. RSD931, a novel anti-tussive agent acting on airway sensory nerves. Br J Pharmacol. 2003;138:407–416. doi: 10.1038/sj.bjp.0705056. PubMed DOI PMC

ANDRE E, GATTI R, TREVISANI M, PRETI D, BARALDI PG, PATACCHINI R, GEPPETTI P. Transient receptor potential ankyrin receptor 1 is a novel target for protussive agents. Br J Pharmacol. 2009;158:1621–1628. doi: 10.1111/j.1476-5381.2009.00438.x. PubMed DOI PMC

BARNES PJ. The problem of cough and development of novel antitussives. Pulm Pharmacol Ther. 2007;20:416–422. doi: 10.1016/j.pupt.2006.11.001. PubMed DOI

BASOGLU OK, BARNES PJ, KHARITONOV SA, PELLEG A. Effect of aerosolized adenosine 5′-triphosphate in smokers and patients with COPD. Chest. 2015;148:430–435. doi: 10.1378/chest.14-2285. PubMed DOI

BAUTISTA DM, PELLEGRINO M, TSUNOZAKI M. TRPA1: a gatekeeper for inflammation. Annu Rev Physiol. 2013;75:181–200. doi: 10.1146/annurev-physiol-030212-183811. PubMed DOI PMC

BELVISI MG, GEPPETTI P. Cough. 7: Current and future drugs for the treatment of chronic cough. Thorax. 2004;59:438–440. doi: 10.1136/thx.2003.013490. PubMed DOI PMC

BENNETT DL, CLARK AJ, HUANG J, WAXMAN SG, DIB-HAJJ SD. The role of voltage-gated sodium channels in pain signalling. Physiol Rev. 2019;99:1079–1151. doi: 10.1152/physrev.00052.2017. PubMed DOI

BIRRELL MA, BELVISI MG, GRACE M, SADOFSKY L, FARUQI S, HELE DJ. TRPA1 agonists evoke coughing in guinea pig and human volunteers. Am J Respir Crit Care Med. 2009;180:1042–1047. doi: 10.1164/rccm.200905-0665OC. PubMed DOI PMC

BONVINI SJ, BELVISI MG. Cough and airway disease: The role of ion channels. Pulm Pharmacol Ther. 2017;47:21–28. doi: 10.1016/j.pupt.2017.06.009. PubMed DOI

BROZMANOVA M, CALKOVSKY V, PLEVKOVA J, BARTOS V, PLANK L, TATAR M. Early and late allergic phase related cough response in sensitized guinea pigs with experimental allergic rhinitis. Physiol Res. 2006;55:577–584. PubMed

BROZMANOVA M, PLEVKOVA J, TATAR M, KOLLARIK M. Cough reflex sensitivity is increased in the guinea pig model of allergic rhinitis. J Physiol Pharmacol. 2008;59(Suppl 6):153–161. PubMed

BROZMANOVA M, MAZUROVA L, RU F, TATAR M, KOLLARIK M. Comparison of TRPA1-versus TRPV1-mediated cough in guinea pigs. Eur J Pharmacol. 2012;689:211–218. doi: 10.1016/j.ejphar.2012.05.048. PubMed DOI PMC

BROZMANOVA M, SVAJDOVA S, PAVELKOVA N, MUROI Y, UNDEM BJ, KOLLARIK M. The voltage-gated sodium channel NaV1.8. blocker A-803467 inhibits cough in the guinea pig. Respir Physiol Neurobiol. 2019;270:103267. doi: 10.1016/j.resp.2019.103267. PubMed DOI

BUDAY T, BROZMANOVA M, BIRINGEROVA Z, GAVLIAKOVA S, POLIACEK I, CALKOVSKY V, SHETTHALLI MV, PLEVKOVA J. Modulation of cough response by sensory inputs from the nose - role of trigeminal TRPA1 versus TRPM8 channels. Cough. 2012;8:11. doi: 10.1186/1745-9974-8-11. PubMed DOI PMC

CANNING BJ, MORI N, MAZZONE SB. Vagal afferent nerves regulating the cough reflex. Respir Physiol Neurobiol. 2006;152:223–242. doi: 10.1016/j.resp.2006.03.001. PubMed DOI

CANNING BJ, CHANG AB, BOLSER DC, SMITH JA, MAZZONE SB, McGARVEY L CHEST Expert Cough Panel. Anatomy and neurophysiology of cough: CHEST Guideline and Expert Panel Report. Chest. 2014;146:1633–1648. doi: 10.1378/chest.14-1481. PubMed DOI PMC

CARR MJ. Plasticity of vagal afferent fibres mediating cough. Pulm Pharmacol Ther. 2004;17:447–451. doi: 10.1016/j.pupt.2004.09.020. PubMed DOI

CARR MJ. Regulation of cough and action potentials by voltage-gated Na channels. Pulm Pharmacol Ther. 2013;26:508–509. doi: 10.1016/j.pupt.2013.07.001. PubMed DOI

CARR MJ, UNDEM BJ. Bronchopulmonary afferent nerves. Respirology. 2003;8:291–301. doi: 10.1046/j.1440-1843.2003.00473.x. PubMed DOI

CATERINA MJ, SCHUMACHER MA, TOMINAGA M, ROSEN TA, LEVINE JD, JULIUS D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816–824. doi: 10.1038/39807. PubMed DOI

CHEN Z, CHEN H, CHEN F, GU D, SUN L, ZHANG W, FAN L, LIN Y, DONG R, LAI K. Vagotomy decreases the neuronal activities of medulla oblongata and alleviates neurogenic inflammation of airways induced by repeated intra-esophageal instillation of HCl in guinea pigs. Physiol Res. 2017;66:1021–1028. doi: 10.33549/physiolres.933574. PubMed DOI

CHOUDRY NB, FULLER RW, PRIDE NB. Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin and histamine. Am Rev Respir Dis. 1989;140:137–141. doi: 10.1164/ajrccm/140.1.137. PubMed DOI

DICPINIGAITIS PV, MORICE AH, BIRRING SS, McGARVEY L, SMITH JA, CANNING BJ, PAGE CP. Antitussive drugs - past, present, and future. Pharmacol Rev. 2014;66:468–512. doi: 10.1124/pr.111.005116. PubMed DOI PMC

DOHERTY MJ, MISTER MG, CALVERLEY PM. Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease. Thorax. 2000;55:643–649. doi: 10.1136/thorax.55.8.643. PubMed DOI PMC

FORD AP, UNDEM BJ. The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders. Front Cell Neurosci. 2013;7:267. doi: 10.3389/fncel.2013.00267. PubMed DOI PMC

FORSBERG K, KARLSSON JA, ZACKRISSON C, PERSSON CG. Selective inhibition of cough and bronchoconstriction in conscious guinea pigs. Respiration. 1992;59:72–76. doi: 10.1159/000196030. PubMed DOI

FOX AJ, LALLOO UG, BELVISI MG, BERNAREGGI M, CHUNG KF, BARNES PJ. Bradykinin-evoked sensitization of airway sensory nerves: A mechanism for ACE-inhibitor cough. Nat Med. 1996;2:814–817. doi: 10.1038/nm0796-814. PubMed DOI

GRACE MS, BIRREL MA, DUBUIS E, MAHER SA, BELVISI MG. Transient receptor potential channels mediate the tussive response to prostaglandin E2 and bradykinin. Thorax. 2012;67:891–900. doi: 10.1136/thoraxjnl-2011-201443. PubMed DOI PMC

GRACE MS, BAXTER M, DUBUIS E, BIRREL MA, BELVISI MG. Transient receptor potential (TRP) channels in the airway: role in airway disease. Br J Pharmacol. 2014;171:2593–2607. doi: 10.1111/bph.12538. PubMed DOI PMC

GRONEBERG DA, NIIMI A, DINH QT, COSIO B, HEW M, FISCHER CHUNG KF. Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough. Am J Respir Crit Care Med. 2004;170:1276–1280. doi: 10.1164/rccm.200402-174OC. PubMed DOI

HENNEL M, BROZMANOVA M, KOLLARIK M. Cough reflex sensitization from esophagus and nose. Pulm Pharmacol Ther. 2015;35:117–121. doi: 10.1016/j.pupt.2015.10.007. PubMed DOI PMC

HOWARD P, CAYTON RM, BRENNAN SR, ANDERSON PB. Lignocaine aerosol and persistent cough. Br Dis Chest. 1977;71:19–24. doi: 10.1016/0007-0971(77)90073-0. PubMed DOI

JARVIS MF, HONORE P, SHIEH CH, CHAPMAN M, JOSHI S, ZHANG XF, KORT M, CARROLL W, MARRON B, ATKONSON R, THOMAS J, LIU D, KRAMBIS M, LIU Y, McGARAUGHTY S, CHU K, ROELOFFS R, ZHONG CH, MIKUSA JP, HERNANDEZ G, GAUVIN D, WADE C, ZHU CH, PAI M, SCANIO M, SHI L, DRIZIN I, GREGG R, MATULENKO M, HAKEEM A, GROSS M, JOHNSON M, MARSH K, WAGONER PK, SULLIVAN JP, FALTYNEK CR, KRAFTE DS. A-803467, a potent and selective NaV1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in rat. Proc Natl Acad Sci USA. 2007;104:8520–8525. doi: 10.1073/pnas.0611364104. PubMed DOI PMC

JI Z, WANG Z, CHEN Z, JIN H, CHEN C, CHAI S, LV H, YANG L, HU Y, DONG R, LAI K. Melatonin attenuates chronic cough mediated by oxidative stress via transient receptor potential melastatin-2 in guinea pigs exposed to particulate matter 2.5. Physiol Res. 2018;67:293–305. doi: 10.33549/physiolres.933654. PubMed DOI

JOSHI SK, HONORE P, HERNANDEZ G, SCHMIDT R, GOMTSYAN A, SCANIO M, KORT M, JARVIS MF. Additive antinociceptive effects of the selective NaV1.8 blocker A-803467 and selective TRPV1 antagonists in rat inflammatory and neuropathic pain models. J Pain. 2009;10:306–315. doi: 10.1016/j.jpain.2008.09.007. PubMed DOI

KAMEI J, TAKAHASHI Y. Involvement of ionotropic purinergic receptors in the histamine-induced enhancement of the cough reflex sensitivity in guinea pigs. Eur J Pharmacol. 2006;547:160–164. doi: 10.1016/j.ejphar.2006.07.034. PubMed DOI

KARLSSON JA. Airway anaesthesia and the cough reflex. Bull Eur Physiopathol Respir. 1987;23(Suppl 10):29–36. PubMed

KARLSSON JA. A role for capsaicin sensitive, tachykinin containing nerves in chronic coughing and sneezing but not in asthma: a hypothesis. Thorax. 1993;48:396–400. doi: 10.1136/thx.48.4.396. PubMed DOI PMC

KELLER JA, McGOVERN AE, MAZZONE SB. Translating cough mechanisms into better cough suppressants. Chest. 2017;152:833–841. doi: 10.1016/j.chest.2017.05.016. PubMed DOI

KOLLARIK M, UNDEM BJ. Mechanisms of acid-induced activation of airway afferent nerve fibres in guinea pigs. J Physiol. 2002;543:591–600. doi: 10.1113/jphysiol.2002.022848. PubMed DOI PMC

KOLLARIK M, UNDEM B. Activation of bronchopulmonary vagal afferent nerves with bradykinin, acid and vanilloid receptor agonists in wild-type and TRPV1−/−mice. J Physiol. 2004;555:115–123. doi: 10.1113/jphysiol.2003.054890. PubMed DOI PMC

KOLLARIK M, BROZMANOVA M. Cough and gastroesophageal reflux: Insight from animal models. Pulm Pharmacol Ther. 2009;22:130–134. doi: 10.1016/j.pupt.2008.12.017. PubMed DOI PMC

KOLLARIK M, RU F, BROZMANOVA M. Vagal afferent nerves with the properties of nociceptors. Auton Neurosci. 2010;153:12–20. doi: 10.1016/j.autneu.2009.08.001. PubMed DOI PMC

KOLLARIK M, SUN H, HERBSTSOMER RA, RU F, KOCMALOVA M, MEEKER SN, UNDEM BJ. Different role of TTX-sensitive voltage-gated sodium channel (NaV 1) subtypes in action potential initiation and conduction in vagal airway nociceptors. J Physiol. 2018;596:1419–1432. doi: 10.1113/JP275698. PubMed DOI PMC

KWONG K, LEE LY. Prostaglandin E2 potentiates a TTX-resistant sodium current in rat capsaicin-sensitive vagal pulmonary sensory neurons. J Physiol. 2005;564:437–450. doi: 10.1113/jphysiol.2004.078725. PubMed DOI PMC

KWONG K, KOLLARIK M, NASSENSTEIN C, RU F, UNDEM BJ. P2X2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating Guinea pig lungs and esophagus. Am J Physiol Lung Cell Mol Physiol. 2008;295:L858–L865. doi: 10.1152/ajplung.90360.2008. PubMed DOI PMC

KWONG K, CARR MJ, GIBBARD A, SAVAGE TJ, SINGH K, JING J, MEEKER S, UNDEM BJ. Voltage-gated sodium channels in nociceptive versus non-nociceptive nodose vagal sensory neurons innervating guinea pig lungs. J Physiol. 2008a;586:1321–1336. doi: 10.1113/jphysiol.2007.146365. PubMed DOI PMC

LAEDERMANN CJ, ABRIEL H, DECOSTERD I. Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes. Front Pharmacol. 2015;6:263. doi: 10.3389/fphar.2015.00263. PubMed DOI PMC

LAI J, PORRECA F, HUNTER JC, GOLD MS. Voltage-gated channels and hyperalgesia. Annu Rev Pharmacol Toxicol. 2004;44:371–397. doi: 10.1146/annurev.pharmtox.44.101802.121627. PubMed DOI

LALLOO UG, FOX AJ, BELVISI MG, CHUNG KF, BARNES PJ. Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs. J Appl Physiol. 1995;79:1082–1087. doi: 10.1152/jappl.1995.79.4.1082. PubMed DOI

LAUDE EA, HIGGINS KS, MORICE AH. A comparative study of the effects of citric acid, capsaicin and resiniferatoxin on the cough challenge in guinea-pig and man. Pulm Pharmacol. 1993;6:171–175. doi: 10.1006/pulp.1993.1023. PubMed DOI

LAVORINI F, SPINA D, WALKER MJ, FRANCIOSI L, PAGE CP, FONTANA GA. Antitussive effect of carcainium chloride in patients with chronic cough and idiopathic interstitial pseudomonias: a pilot study. Pulm Pharmacol Ther. 2016;40:91–94. doi: 10.1016/j.pupt.2016.08.001. PubMed DOI

LEE LY, MORTON RF. Histamine enhances vagal pulmonary C fiber responses to capsaicin and lung inflation. Respir Physiol. 1993;93:83–96. doi: 10.1016/0034-5687(93)90070-Q. PubMed DOI

LEVINE JD, ALESSANDRI-HABER N. TRP channels: Targets for the relief of pain. Biochim Biophys Acta. 2007;1772:989–1003. doi: 10.1016/j.bbadis.2007.01.008. PubMed DOI

LIM KG, RANK MA, HAHN PY, KEOGH KA, MORGENTHALER TI, OLSON EJ. Long-term safety of nebulized lidocaine for adults with difficult-to-control chronic cough: a case series. Chest. 2013;143:1060–1065. doi: 10.1378/chest.12-1533. PubMed DOI

MAZZONE SB. An overview of the sensory receptors regulating cough. Cough. 2005;1:2. doi: 10.1186/1745-9974-1-2. PubMed DOI PMC

MAZZONE SB, UNDEM BJ. Cough sensors. V. Pharmacological modulation of cough sensors. Handb Exp Pharmacol. 2009;187:99–127. doi: 10.1007/978-3-540-79842-2_6. PubMed DOI

MAZZONE SB, UNDEM BJ. Vagal Afferent innervation of the airways in health and disease. Physiol Rev. 2016;96:975–1024. doi: 10.1152/physrev.00039.2015. PubMed DOI PMC

McKEMY DD, NEUHAUSSER WM, JULIUS D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002;416:52–58. doi: 10.1038/nature719. PubMed DOI

MORICE AH, MARSHALL AE, HIGGINS KS, GRATTAN TJ. Effect of inhaled menthol on citric acid induced cough in normal subjects. Thorax. 1994;49:1024–1026. doi: 10.1136/thx.49.10.1024. PubMed DOI PMC

MORICE AH, GEPPETTI P. Cough. 5: the type 1 vanilloid receptor: a sensory receptor for cough. Thorax. 2004;59:257–258. doi: 10.1136/thx.2003.013482. PubMed DOI PMC

MORICE AH, FONTANA GA, BELVISI MG, BIRRING SS, CHUNG KF, DICPINIGAITIS PV, KASTELIK JA, McGARVEY LP, SMITH A, TATAR M, WIDDICOMBE J. ERS guidelines on the assessment of cough. Eur Respir J. 2007;29:1256–1276. doi: 10.1183/09031936.00101006. PubMed DOI

MUROI Y, RU F, KOLLARIK M, CANNING BJ, HUGHES SA, WALSH S, SIGG M, CARR MJ, UNDEM BJ. Selective silencing of NaV1.7 decreases excitability and conduction in vagal sensory neurons. J Physiol. 2011;589:5663–5676. doi: 10.1113/jphysiol.2011.215384. PubMed DOI PMC

MUROI Y, RU F, CHOU YL, CARR MJ, UNDEM BJ, CANNING BJ. Selective inhibition of vagal afferent nerve pathways regulating cough using Nav 1.7 shRNA silencing in guinea pig nodose ganglia. Am J Physiol Regul Integr Comp Physiol. 2013;304:R1017–R1023. doi: 10.1152/ajpregu.00028.2013. PubMed DOI PMC

MUROI Y, UNDEM BJ. Targeting voltage gated sodium channels NaV1.7, NaV1.8, and NaV1.9 for treatment of pathological cough. Lung. 2014;192:15–20. doi: 10.1007/s00408-013-9533-x. PubMed DOI PMC

NASSENSTEIN C, KWONG K, TAYLOR-CLARK T, KOLLARIK M, MACGLASHAN D, BRAUN A, UNDEM BJ. Expression and function of the ion channel TRPA1 in vagal afferent nerves innervating mouse lung. J Physiol. 2008;586:1595–1604. doi: 10.1113/jphysiol.2007.148379. PubMed DOI PMC

NIIMI A, CHUNG KF. Evidence for neuropathic processes in chronic cough. Pulm Pharmacol Ther. 2015;35:100–104. doi: 10.1016/j.pupt.2015.10.004. PubMed DOI

PATIL MJ, SUN H, MEEKER S, UNDEM BJ. Targeting C-fibres for peripheral acting antitussive drugs. Pulm Pharmacol Ther. 2019;56:15–19. doi: 10.1016/j.pupt.2019.03.002. PubMed DOI PMC

PECOVA R, JAVORKOVA N, KUDLICKA J, TATAR M. Tussigenic agents in the measurement of cough reflex sensitivity. J Physiol Pharmacol. 2007;58(Suppl 5):531–538. PubMed

PECOVA R, ZUCHA J, PEC M, NEUSCHLOVA M, HANZEL P, TATAR M. Cough reflex sensitivity testing in seasonal allergic rhinitis patients and healthy volunteers. J Physiol Pharmacol. 2008;59(Suppl 6):557–564. PubMed

PLEVKOVA J, BROZMANOVA M, PECOVA R, TATAR M. Effects of intranasal capsaicin challenge on cough reflex in healthy human volunteers. J Physiol Pharmacol. 2004;55(Suppl 3):101–106. PubMed

PLEVKOVA J, KOLLARIK M, BROZMANOVA M, REVALLO M, VARECHOVA S, TATAR M. Modulation of experimentally-induced cough by stimulation of nasal mucosa in cats and guinea pigs. Respir Physiol Neurobiol. 2004a;142:225–235. doi: 10.1016/j.resp.2004.06.006. PubMed DOI

PLEVKOVA J, KOLLARIK M, POLIACEK I, BROZMANOVA M, SURDENIKOVA L, TATAR M, MORI M, CANNING B. The role of trigeminal nasal TRPM8-expressing afferent neurons in the antitussive effects of menthol. J Appl Physiol. 2013;115:268–274. doi: 10.1152/japplphysiol.01144.2012. PubMed DOI PMC

SANDERS RV, KIRKPATRICK MB. Prolonged suppression of cough after inhalation of lidocaine in a patient with sarcoidosis. JAMA. 1984;252:2456–2457. doi: 10.1001/jama.252.17.2456. PubMed DOI

SMITH J, OWEN E, EARIS J, WOODCOCK A. Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2006;117:831–835. doi: 10.1016/j.jaci.2005.09.055. PubMed DOI

SMITH JA, McGARVEY LPA, BADRI H, SATIA I, WARREN F, SIEDERER S, LIEFAARD L, MURDOCH RD, POVEZ K, MARKS-KONCYALIK J. Effects of a novel sodium channel blocker, GSK2339345, in patients with refractory chronic cough. Int J Clin Pharmacol Ther. 2017;55:712–719. doi: 10.5414/CP202804. PubMed DOI

SONG WJ, MORICE AH. Cough hypersensitivity syndrome: a few more steps forward. Allergy Asthma Immunol Res. 2017;9:394–402. doi: 10.4168/aair.2017.9.5.394. PubMed DOI PMC

STRICKLAND IT, MARTINDALE JC, WOODHAMS PL, REEVE AJ, CHESSELL IP, McQEEN DS. Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur J Pain. 2008;12:564–572. doi: 10.1016/j.ejpain.2007.09.001. PubMed DOI

SUN H, KOLLARIK M, UNDEM BJ. Blocking voltage-gated sodium channels as a strategy to suppress pathological cough. Pulm Pharmacol Ther. 2017;47:38–41. doi: 10.1016/j.pupt.2017.05.010. PubMed DOI

SVAJDOVA S, BUDAY T, BROZMANOVA M. Lidocaine, a non-selective inhibitor of voltage-gated sodium channels, blocks chemically-induced cough in awake naive guinea pigs. Adv Exp Med Biol. 2019;1160:1–9. doi: 10.1007/5584_2018_326. PubMed DOI

TAYLOR-CLARK TE, UNDEM BJ, MacGLASHAN DW, GHATTA S, CARR MJ, McALEXANDER MA. Prostaglandin-induced activation of nociceptive neurons via direct interaction with transient receptor potential A1 (TRPA1) Mol Pharmacol. 2008;73:274–281. doi: 10.1124/mol.107.040832. PubMed DOI

TAYLOR-CLARK TE, NASSENSTEIN C, McALEXANDER MA, UNDEM BJ. TRPA1: A potential target for antitussive therapy. Pulm Pharmacol Ther. 2009;22:71–74. doi: 10.1016/j.pupt.2008.12.019. PubMed DOI

TAYLOR-CLARK TE. Peripheral neural circuitry in cough. Curr Opin Pharmacol. 2015;22:9–17. doi: 10.1016/j.coph.2015.02.001. PubMed DOI PMC

TROCHTENBERG S. Nebulized lidocaine in the treatment of refractory cough. Chest. 1994;105:1592–1593. doi: 10.1378/chest.105.5.1592. PubMed DOI

TRUESDALE K, JURDI A. Nebulized lidocaine in the treatment of intractable cough. Am J Hosp Palliat Care. 2013;30:587–589. doi: 10.1177/1049909112458577. PubMed DOI

UNDEM BJ, ZACCONE E, McGARWAY L, MAZZONE SB. Neural dysfunction following respiratory viral infection as a cause of chronic cough hypersensitivity. Pharmacol Ther. 2015;33:52–56. doi: 10.1016/j.pupt.2015.06.006. PubMed DOI PMC

VENKATASAMY R, McKENZIE A, PAGE CP, WALKER MJ, SPINA D. Use of within-group designs to test antitussive drugs in conscious guinea-pigs. J Pharmacol Toxicol Methods. 2010;61:157–162. doi: 10.1016/j.vascn.2010.02.015. PubMed DOI

WEST PW, CANNING BJ, MERLO-PICH E, WOODCOCK AA, SMITH JA. Morphologic characterization of nerves in whole-mount airway biopsies. Am J Respir Crit Care Med. 2015;192:30–39. doi: 10.1164/rccm.201412-2293OC. PubMed DOI PMC

ZACCONE EJ, LIEU TM, MUROI Y, POTENZIERI C, UNDEM BE, GAO P, HAN L, CANNING BJ, UNDEM BJ. Parainfluenza 3-induced cough hypersensitivity in the guinea pig airways. PloS One. 2016;11:e015552. doi: 10.1371/journal.pone.0155526. PubMed DOI PMC

Methods of Cough Assessment and Objectivization

Legacy of Prof. Juraj Korpáš: International Impact of Slovak School of Experimental Respirology