Regulation of Cough by Voltage-Gated Sodium Channels in Airway Sensory Nerves

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Chronic cough is a significant clinical problem in many patients. Current cough suppressant therapies are largely ineffective and have many dangerous adverse effects. Therefore, the identification of novel therapeutic targets and strategies for chronic cough treatment may lead to development of novel effective antitussive therapies with fewer adverse effects. The experimental research in the area of airway sensory nerves suggests that there are two main vagal afferent nerve subtypes that can directly activate cough – extrapulmonary airway C-fibres and Aδ-fibres (described as cough receptors) innervating the trachea. There are different receptors on the vagal nerve terminals that can trigger coughing, such as TRP channels and P2X2/3 receptors. However, in many patients with chronic respiratory diseases multiple activation of these receptors could be involved and it is also difficult to target these receptors. For that reason, a strategy that would inhibit cough-triggering nerve afferents regardless of activated receptors would be of great benefit. In recent years huge progress in understanding of voltage-gated sodium channels (NaVs) leads to a hypothesis that selective targeting of NaVs in airways may represent an effective treatment of pathological cough. The NaVs (NaV1.1 – NaV1.9) are essential for initiation and conduction of action potentials in these nerve fibres. Effective blocking of NaVs will prevent communication between airways and central nervous system and that would inhibit provoked cough irrespective to stimuli. This review provides an overview of airway afferent nerve subtypes that have been described in respiratory tract of human and in animal models. Moreover, the review highlights the current knowledge about cough, the sensory nerves involved in cough, and the voltage-gated sodium channels as a novel neural target in regulation of cough.

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  • 1. 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 (6): 1633-1648.

  • 2. Muroi Y Undem BJ. Targeting voltage gated sodium channels NaV1.7 Na V1.8 and Na V1.9 for treatment of pathological cough. Lung 2014; 192 (1): 15-20.

  • 3. 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.

  • 4. 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 (8): 1419-1432.

  • 5. Mazzone SB Undem BJ. Vagal Afferent Innervation of the Airways in Health and Disease. Physiol Rev 2016; 96 (3): 975-1024.

  • 6. Baker CV. The embryology of vagal sensory neurons. In: Advances in Vagal Afferent Neurobiology Undem BJ Weinreich D editors. Boca Raton FL: CRC; 2005. p. 3–26.

  • 7. Nassenstein C Taylor-Clark TE Myers AC Ru F Nandigama R Bettner W Undem BJ. Phenotypic distinctions between neural crest and placodal derived vagal C-fibres in mouse lungs. J Physiol 2010; 588 (Pt 23): 4769-4783.

  • 8. Hodes R. Linear relationship between fiber diameter and velocity of conduction in giant axon of squid. J Neurophysiol 1953; 16 (2): 145-154.

  • 9. Canning BJ Undem BJ. Evidence that distinct neural pathways mediate parasympathetic contractions and relaxations of guinea-pig trachealis. J Physiol 1993; 471: 25-40.

  • 10. Canning BJ Mazzone SB Meeker SN Mori N Reynolds SM Undem BJ. Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J Physiol 2004; 557 (Pt 2): 543-558.

  • 11. Undem BJ Chuaychoo B Lee MG Weinreich D Myers AC Kollarik M. Subtypes of vagal afferent C-fibres in guinea-pig lungs. J Physiol 2004; 556 (Pt 3): 905–917.

  • 12. 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 2008; 586 (5): 1321-1336.

  • 13. Kollarik M Undem BJ. Mechanisms of acid-induced activation of airway afferent nerve fibres in guinea-pig. J Physiol 2002; 543 (Pt 2): 591-600.

  • 14. Lin YJ Lin RL Ruan T Khosravi M Lee LY. A synergistic effect of simultaneous TRPA1 and TRPV1 activations on vagal pulmonary C-fiber afferents. J Appl Physiol (1985) 2015; 118 (3): 273-281.

  • 15. Kollarik M Dinh QT Fischer A Undem BJ. Capsaicin-sensitive and -insensitive vagal bronchopulmonary C-fibres in the mouse. J Physiol 2003; 551 (Pt 3): 869-879.

  • 16. Riccio MM Kummer W Biglari B Myers AC Undem BJ. Interganglionic segregation of distinct vagal afferent fibre phenotypes in guinea-pig airways. J Physiol 1996; 496 (Pt 2): 521-530.

  • 17. Kajekar R Proud D Myers AC Meeker SN Undem BJ. Characterization of vagal afferent subtypes stimulated by bradykinin in guinea pig trachea. J Pharmacol Exp Ther 1999; 289 (2): 682-687.

  • 18. Yu S Undem BJ Kollarik M. Vagal afferent nerves with nociceptive properties in guinea-pig oesophagus. J Physiol 2005; 563 (Pt 3): 831-842.

  • 19. Kollarik M Ru F Brozmanova M. Vagal afferent nerves with the properties of nociceptors. Autonomic Neuroscience: Basic and Clinical 2010; 153: 12–20.

  • 20. Coleridge JC Coleridge HM. Afferent vagal C fibre innervation of the lungs and airways and its functional significance. Rev Physiol Biochem Pharmacol 1984; 99: 1–110.

  • 21. 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 (6653): 816-824.

  • 22. Jordt SE Bautista DM Chuang HH McKemy DD Zygmunt PM Högestätt ED Meng ID Julius D. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 2004; 427 (6971): 260-265.

  • 23. Bautista DM Jordt SE Nikai T Tsuruda PR Read AJ Poblete J Yamoah EN Basbaum AI Julius D. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 2006; 124 (6): 1269-1282.

  • 24. Nassenstein C Kwong K Taylor-Clark T Kollarik M Macglashan DM Braun A Undem BJ. Expression and function of the ion channel TRPA1 in vagal afferent nerves innervating mouse lungs. J Physiol 2008; 586 (6): 1595-1604.

  • 25. 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.

  • 26. Kollarik M Undem BJ. Activation of bronchopulmonary vagal afferent nerves with bradykinin acid and vanilloid receptor agonists in wild-type and TRPV1-/- mice. J Physiol 2004; 555 (Pt 1): 115-123.

  • 27. Gu Q Lee LY. Characterization of acid signaling in rat vagal pulmonary sensory neurons. Am J Physiol Lung Cell Mol Physiol 2006; 291 (1): L58-L65.

  • 28. Coleridge HM Coleridge JC. Impulse activity in afferent vagal C-fibres with endings in the intrapulmonary airways of dogs. Respir Physiol 1977; 29 (2): 125-142.

  • 29. Chuaychoo B Lee MG Kollarik M Undem BJ. Effect of 5-hydroxy-tryptamine on vagal C-fiber subtypes in guinea pig lungs. Pulm Pharmacol Ther 2005; 18 (4): 269–276.

  • 30. Chuaychoo B. Lee MG Kollarik M Pullmann R Jr Undem BJ (2006). Evidence for both adenosine A1 and A2A receptors activating single vagal sensory C-fibres in guinea pig lungs. J Physiol; 575 (Pt 2): 481–490.

  • 31. 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 (5): L858-L865.

  • 32. Tatar M Webber SE Widdicombe JG. Lung C-fibre receptor activation and defensive reflexes in anaesthetized cats. J Physiol 1988; 402: 411-420.

  • 33. Tatar M Sant’Ambrogio G Sant’Ambrogio FB. Laryngeal and tracheobronchial cough in anesthetized dogs. J Appl Physiol (1985) 1994; 76 (6): 2672-2679.

  • 34. Karlsson JA Sant’Ambrogio FB Forsberg K Palecek F Mathew OP Sant’Ambrogio G. Respiratory and cardiovascular effects of inhaled and intravenous bradykinin PGE2 and PGF2 alpha in dogs. J Appl Physiol (1985) 1993; 74 (5): 2380-2386.

  • 35. Hunter DD Undem BJ. Identification and substance P content of vagal afferent neurons innervating the epithelium of the guinea pig trachea. Am J Respir Crit Care Med 1999; 159 (6): 1943-1948.

  • 36. Canning BJ Mori N Mazzone SB. Vagal afferent nerves regulating the cough reflex. Respir Physiol Neurobiol 2006; 152 (3): 223-242.

  • 37. Mazzone SB Reynolds SM Mori N Kollarik M Farmer DG Myers AC Canning BJ. Selective expression of a sodium pump isozyme by cough receptors and evidence for its essential role in regulating cough. J Neurosci 2009; 29 (43): 13662-13671.

  • 38. 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 (1): 30-39.

  • 39. Schelegle ES Green JF. An overview of the anatomy and physiology of slowly adapting pulmonary stretch receptors. Respir Physiol 2001; 125 (1-2): 17-31.

  • 40. Widdicombe J. Functional morphology and physiology of pulmonary rapidly adapting receptors (RARs). Anat Rec A Discov Mol Cell Evol Biol 2003; 270 (1): 2-10.

  • 41. Liu J Yu J. Spectrum of myelinated pulmonary afferents (II). Am J Physiol Regul Integr Comp Physiol 2013; 305 (9): R1059-R1064.

  • 42. Lee LY Yu J. Sensory nerves in lung and airways. Compr Physiol 2014; 4(1): 287-324.

  • 43. Mills JE Sellick H Widdicombe JG. Vagal deflation reflexes mediated by lung irritant receptors. J Physiol 1969; 204 (2): 137P.

  • 44. Sellick H Widdicombe JG. The activity of lung irritant receptors during pneumothorax hyperpnoea and pulmonary vascular congestion. J Physiol 1969; 203 (2): 359-381.

  • 45. Dixon M Jackson DM Richards IM. The effects of H1- and H2-receptor agonists and antagonists on total lung resistance dynamic lung compliance and irritant receptor discharge in the anaesthetized dog. Br J Pharmacol 1979; 66 (2): 203-209.

  • 46. Ford AP Undem BJ Birder LA Grundy D Pijacka W Paton JF. P2X3 receptors and sensitization of autonomic reflexes. Auton Neurosci 2015; 191: 16-24.

  • 47. Schelegle ES. Functional morphology and physiology of slowly adapting pulmonary stretch receptors. Anat Rec A Discov Mol Cell Evol Biol 2003; 270 (1): 11-16.

  • 48. Shinagawa K Kojima M Ichikawa K Hiratochi M Aoyagi S Akahane M. Participation of thromboxane A(2) in the cough response in guinea-pigs: antitussive effect of ozagrel. Br J Pharmacol 2000; 131 (2): 266–270.

  • 49. El-Hashim AZ Amine SA. The role of substance P and bradykinin in the cough reflex and bronchoconstriction in guineapigs. Eur J Pharmacol 2005; 513 (1–2): 125–133.

  • 50. Widdicombe JG. Airway receptors. Respir Physiol 2001; 125 (1-2): 3-15.

  • 51. Yu J Wang YF Zhang JW. Structure of slowly adapting pulmonary stretch receptors in the lung periphery. J Appl Physiol (1985) 2003; 95 (1): 385-393.

  • 52. Widdicombe JG. Neurophysiology of the cough reflex. Eur Respir J 1995; 8 (7): 1193-1202.

  • 53. Fontana GA Pantaleo T Lavorini F Mutolo D Polli G Pistolesi M. Coughing in laryngectomized patients. Am J Respir Crit Care Med 1999; 160 (5 Pt 1): 1578-1584.

  • 54. Young EC Smith JA. Pharmacologic therapy for cough. Curr Opin Pharmacol 2011; 11(3): 224-230.

  • 55. 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

  • 56. Song WJ Morice AH. Cough Hypersensitivity Syndrome: A Few More Steps Forward. Allergy Asthma Immunol Res 2017; 9 (5): 394-402.

  • 57. Bonvini SJ Birrell MA Smith JA Belvisi MG. Targeting TRP channels for chronic cough: from bench to bedside. Naunyn Schmiedebergs Arch Pharmacol 2015; 388 (4): 401-420.

  • 58. Keller JA McGovern AE Mazzone SB. Translating Cough Mechanisms Into Better Cough Suppressants. Chest 2017; 152 (4): 833-841.

  • 59. Belvisi MG Geppetti P. Cough. 7: Current and future drugs for the treatment of chronic cough. Thorax 2004; 59 (5): 438-440.

  • 60. Barnes PJ. The problem of cough and development of novel antitussives. Pulm Pharmacol Ther 2007; 20 (4): 416-422.

  • 61. 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 (4): 831-835.

  • 62. Noda M Suzuki H Numa S Stühmer W. A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II. FEBS Lett 1994; 259 (1): 213-216.

  • 63. Habib AM Wood JN Cox JJ. Sodium channels and pain. Handb Exp Pharmacol 2015; 227: 39-56.

  • 64. Colquhoun D Ritchie JM. The kinetics of the interaction between tetrodotoxin and mammalian nonmyelinated nerve fibers. Mol Pharmacol 1972; 8 (3): 285-292.

  • 65. Lago J Rodríguez LP Blanco L Vieites JM Cabado AG. Tetrodotoxin an Extremely Potent Marine Neurotoxin: Distribution Toxicity Origin and Therapeutical Uses. Mar Drugs 2015; 13 (10): 6384–6406.

  • 66. Muroi Y Ru F Kollarik M Canning BJ Hughes SA Walsh S Sigg M Carr MJ Undem BJ. Selective silencing of Na(V)1.7 decreases excitability and conduction in vagal sensory neurons. J Phy siol 2011; 589 (Pt 23): 5663-5676.

  • 67. Laedermann CJ Abriel H Decosterd I. Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes. Front Pharmacol 2015; 6: 263.

  • 68. 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 (11): R1017-R1023.

  • 69. Goldberg YP MacFarlane J MacDonald ML Thompson J Dube MP Mattice M Fraser R Young C Hossain S Pape T Payne B Radomski C Donaldson G Ives E Cox J Younghusband HB Green R Duff A Boltshauser E Grinspan GA Dimon JH Sibley BG Andria G Toscano E Kerdraon J Bowsher D Pimstone SN Samuels ME Sherrington R Hayden MR. Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet 2007; 71 (4): 311-319.

  • 70. Weiss J Pyrski M Jacobi E Bufe B Willnecker V Schick B Zizzari P Gossage SJ Greer CA Leinders-Zufall T Woods CG Wood JN Zufall F. Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature 2011; 472 (7342): 186-190.

  • 71. Kanellopoulos AH Matsuyama A. Voltage-gated sodium channels and pain-related disorders. Clin Sci (Lond) 2016; 130 (24): 2257-2265.

  • 72. Jarvis MF Honore P Shieh CC Chapman M Joshi S Zhang XF Kort M Carroll W Marron B Atkinson R Thomas J Liu D Krambis M Liu Y McGaraughty S Chu K Roeloffs R Zhong C Mikusa JP Hernandez G Gauvin D Wade C Zhu C 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 the rat. Proc Natl Acad Sci U S A 2007; 104 (20): 8520-8525.

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