Cell and Tissue Research

, Volume 367, Issue 3, pp 571–590 | Cite as

The nervous system of airways and its remodeling in inflammatory lung diseases

  • Katrin Julia Audrit
  • Lucas Delventhal
  • Öznur Aydin
  • Christina NassensteinEmail author


Inflammatory lung diseases are associated with bronchospasm, cough, dyspnea and airway hyperreactivity. The majority of these symptoms cannot be primarily explained by immune cell infiltration. Evidence has been provided that vagal efferent and afferent neurons play a pivotal role in this regard. Their functions can be altered by inflammatory mediators that induce long-lasting changes in vagal nerve activity and gene expression in both peripheral and central neurons, providing new targets for treatment of pulmonary inflammatory diseases.


Allergic asthma Chronic obstructive lung disease (COPD) Peripheral sensitization Central sensitization Transient receptor potential ankyrin 1 (TRPA1) Transient receptor potential vanilloid 1 (TRPV1) Vagal ganglia Nucleus tractus solitarii (NTS) 



The authors like to thank Wolfgang Kummer, Institute of Anatomy and Cell Biology, Giessen, for critical discussion of this review.

Compliance with ethical standards

Funding information

This work was funded by the German Center for Lung Research.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abdullah H, Heaney LG, Cosby SL, McGarvey LPA (2014) Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity. Thorax 69(1):46–54PubMedCrossRefGoogle Scholar
  2. Abdulqawi R, Dockry R, Holt K, Layton G, McCarthy BG, Ford AP, Smith JA (2015) P2X3 receptor antagonist (AF-219) in refractory chronic cough. A randomised, double-blind, placebo-controlled phase 2 study. Lancet 385(9974):1198–1205PubMedCrossRefGoogle Scholar
  3. Adamko DJ, Yost BL, Gleich GJ, Fryer AD, Jacoby DB (1999) Ovalbumin sensitization changes the inflammatory response to subsequent parainfluenza infection. Eosinophils mediate airway hyperresponsiveness, m(2) muscarinic receptor dysfunction, and antiviral effects. J Exp Med 190(10):1465–1478PubMedPubMedCentralCrossRefGoogle Scholar
  4. American Thoracic Society (1999) Dyspnea. Mechanisms, assessment, and management: a consensus statement. Am J Res Crit Care Med 159(1):321–340CrossRefGoogle Scholar
  5. Anand U, Otto WR, Facer P, Zebda N, Selmer I, Gunthorpe MJ, Chessell IP, Sinisi M, Birch R, Anand P (2008) TRPA1 receptor localisation in the human peripheral nervous system and functional studies in cultured human and rat sensory neurons. Neurosci Lett 438(2):221–227PubMedCrossRefGoogle Scholar
  6. Bai TR, Bramley AM (1993) Effect of an inhibitor of nitric oxide synthase on neural relaxation of human bronchi. Am J Physiol 264(5 Pt 1):L425–L430PubMedGoogle Scholar
  7. Balentova S, Conwell S, Myers AC (2013) Neurotransmitters in parasympathetic ganglionic neurons and nerves in mouse lower airway smooth muscle. Resp Physiol Neurobiol 189(1):195–202CrossRefGoogle Scholar
  8. Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41(6):849–857PubMedCrossRefGoogle Scholar
  9. Banzett RB, Lansing RW, Brown R, Topulos GP, Yager D, Steele SM, Londono B, Loring SH, Reid MB, Adams L (1990) ‘Air hunger’ from increased PCO2 persists after complete neuromuscular block in humans. Respir Physiol 81(1):1–17PubMedCrossRefGoogle Scholar
  10. Barnes PJ (1991) Neurogenic inflammation in airways. Int Arch Allergy Appl Immunol 94(1–4):303–309PubMedCrossRefGoogle Scholar
  11. Barnes PJ (1992) Neural mechanisms in asthma. Br Med Bull 48(1):149–168PubMedCrossRefGoogle Scholar
  12. Barnes PJ (1993) Muscarinic receptor subtypes in airways. Life Sci 52(5–6):521–527PubMedCrossRefGoogle Scholar
  13. Basoglu OK, Barnes PJ, Kharitonov SA, Pelleg A (2015) Effects of Aerosolized Adenosine 5′-Triphosphate in Smokers and Patients With COPD. Chest 148(2):430–435PubMedCrossRefGoogle Scholar
  14. Bautista DM, Jordt S-E, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EN, Basbaum AI, Julius D (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124(6):1269–1282PubMedCrossRefGoogle Scholar
  15. Bellingham MC, Lipski J (1992) Morphology and electrophysiology of superior laryngeal nerve afferents and postsynaptic neurons in the medulla oblongata of the cat. Neuroscience 48(1):205–216PubMedCrossRefGoogle Scholar
  16. Belvisi MG, Birrell MA, Khalid S, Wortley MA, Dockry R, Coote J, Holt K, Dubuis E, Kelsall A, Maher SA, Bonvini S, Woodcock A, Smith JA (2016) Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies. Am J Respir Crit Care Med 193(12):1364–1372PubMedPubMedCentralCrossRefGoogle Scholar
  17. Binks AP, Evans KC, Reed JD, Moosavi SH, Banzett RB (2014) The time-course of cortico-limbic neural responses to air hunger. Resp Physiol Neurobiol 204:78–85CrossRefGoogle Scholar
  18. Black JL (1991) Pharmacology of airway smooth muscle in chronic obstructive pulmonary disease and in asthma. Am Rev Resp Dis 143(5 Pt 1):1177–1181PubMedCrossRefGoogle Scholar
  19. Boot JD, de Haas S, Tarasevych S, Roy C, Wang L, Amin D, Cohen J, Sterk PJ, Miller B, Paccaly A, Burggraaf J, Cohen AF, Diamant Z (2007) Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma. Am J Respir Crit Care Med 175(5):450–457PubMedCrossRefGoogle Scholar
  20. Bowden JJ, Gibbins IL (1992) Vasoactive intestinal peptide and neuropeptide Y coexist in non-noradrenergic sympathetic neurons to guinea pig trachea. J Auton Nerv Syst 38(1):1–19PubMedCrossRefGoogle Scholar
  21. Braun A, Appel E, Baruch R, Herz U, Botchkarev V, Paus R, Brodie C, Renz H (1998) Role of nerve growth factor in a mouse model of allergic airway inflammation and asthma. Eur J Immunol 28(10):3240–3251PubMedCrossRefGoogle Scholar
  22. Braun A, Lommatzsch M, Mannsfeldt A, Neuhaus-Steinmetz U, Fischer A, Schnoy N, Lewin GR, Renz H (1999) Cellular sources of enhanced brain-derived neurotrophic factor production in a mouse model of allergic inflammation. Am J Resp Cell Mol Biol 21(4):537–546CrossRefGoogle Scholar
  23. Brouns I, Pintelon I, De Proost I, Alewaters R, Timmermans JP, Adriaensen D (2006) Neurochemical characterisation of sensory receptors in airway smooth muscle: comparison with pulmonary neuroepithelial bodies. Histochem Cell Biol 125(4):351–367PubMedCrossRefGoogle Scholar
  24. Brozmanova M, Mazurova L, Ru F, Tatar M, Hu Y, Yu S, Kollarik M (2016) Mechanisms of the adenosine A2A receptor-induced sensitization of esophageal C fibers. Am J Physiol Gastrointest Liver Physiol 310(3):G215–G223PubMedGoogle Scholar
  25. Burnstock G (2012) Discovery of purinergic signalling, the initial resistance and current explosion of interest. Br J Pharmacol 167(2):238–255PubMedPubMedCentralCrossRefGoogle Scholar
  26. Burnstock G, Kennedy C (2011) P2X receptors in health and disease. Adv Pharmacol 61:333–372PubMedCrossRefGoogle Scholar
  27. Caceres AI, Brackmann M, Elia MD, Bessac BF, del Camino D, D’Amours M, Witek JS, Fanger CM, Chong JA, Hayward NJ, Homer RJ, Cohn L, Huang X, Moran MM, Jordt S-E (2009) A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc Natl Acad Sci U S A 106(22):9099–9104PubMedPubMedCentralCrossRefGoogle Scholar
  28. Canning BJ, Undem BJ (1993) Relaxant innervation of the guinea-pig trachealis: demonstration of capsaicin-sensitive and -insensitive vagal pathways. J Physiol 460:719–739PubMedPubMedCentralCrossRefGoogle Scholar
  29. Canning BJ, Undem BJ, Karakousis PC, Dey RD (1996) Effects of organotypic culture on parasympathetic innervation of guinea pig trachealis. Am J Physiol 271(5 Pt 1):L698–L706PubMedGoogle Scholar
  30. Canning BJ, Mazzone SB, Meeker SN, Mori N, Reynolds SM, Undem BJ (2004) Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J Physiol 557(Pt 2):543–558PubMedPubMedCentralCrossRefGoogle Scholar
  31. Canning BJ, Reynolds SM, Anukwu LU, Kajekar R, Myers AC (2002) Endogenous neurokinins facilitate synaptic transmission in guinea pig airway parasympathetic ganglia. Am J Physiol Regul Integr Comp Physiol 283(2):R320–R330PubMedCrossRefGoogle Scholar
  32. Canning BJ, Reynolds SM, Mazzone SB (2001) Multiple mechanisms of reflex bronchospasm in guinea pigs. J Appl Physiol 91(6):2642–2653PubMedGoogle Scholar
  33. Cantero-Recasens G, Gonzalez JR, Fandos C, Duran-Tauleria E, Smit LAM, Kauffmann F, Anto JM, Valverde MA (2010) Loss of function of transient receptor potential vanilloid 1 (TRPV1) genetic variant is associated with lower risk of active childhood asthma. J Biol Chem 285(36):27532–27535PubMedPubMedCentralCrossRefGoogle Scholar
  34. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389(6653):816–824PubMedCrossRefGoogle Scholar
  35. Caulfield MP (1993) Muscarinic receptors--characterization, coupling and function. Pharmacol Ther 58(3):319–379PubMedCrossRefGoogle Scholar
  36. Chamberlain SAF, Garrod R, Douiri A, Masefield S, Powell P, Bucher C, Pandyan A, Morice AH, Birring SS (2015) The impact of chronic cough: a cross-sectional European survey. Lung 193(3):401–408PubMedCrossRefGoogle Scholar
  37. Chang RB, Strochlic DE, Williams EK, Umans BD, Liberles SD (2015) Vagal Sensory Neuron Subtypes that Differentially Control Breathing. Cell 161(3):622–633PubMedPubMedCentralCrossRefGoogle Scholar
  38. Chen CY, Bonham AC, Schelegle ES, Gershwin LJ, Plopper CG, Joad JP (2001) Extended allergen exposure in asthmatic monkeys induces neuroplasticity in nucleus tractus solitarius. J Allergy Clin Immunol 108(4):557–562PubMedCrossRefGoogle Scholar
  39. Chen S-D, Wen Z-H, Chang W-K, Chan K-H, Tsou M-T, Sung C-S, Tang G-J (2008) Acute effect of methylprednisolone on the brain in a rat model of allergic asthma. Neurosci Lett 440(2):87–91PubMedCrossRefGoogle Scholar
  40. Chen Z, Eldridge FL, Wagner PG (1991) Respiratory-associated rhythmic firing of midbrain neurones in cats: relation to level of respiratory drive. J Physiol 437:305–325PubMedPubMedCentralCrossRefGoogle Scholar
  41. Chizh BA, O’Donnell MB, Napolitano A, Wang J, Brooke AC, Aylott MC, Bullman JN, Gray EJ, Lai RY, Williams PM, Appleby JM (2007) The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans. Pain 132(1–2):132–141PubMedCrossRefGoogle Scholar
  42. Choudry NB, Fuller RW, Pride NB (1989) Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin, and histamine. Am Rev Respir Dis 140(1):137–141PubMedCrossRefGoogle Scholar
  43. Colasurdo GN, Hemming VG, Prince GA, Gelfand AS, Loader JE, Larsen GL (1998) Human respiratory syncytial virus produces prolonged alterations of neural control in airways of developing ferrets. Am Resp Crit Care Med 157(5):1506–1511CrossRefGoogle Scholar
  44. Coleridge HM, Coleridge JC, Schultz HD (1989) Afferent pathways involved in reflex regulation of airway smooth muscle. Pharmacol Ther 42(1):1–63PubMedCrossRefGoogle Scholar
  45. Corboz MR, Rivelli MA, Eckel SP (2010) Bronchoconstrictor effect of the tachykinin NK(3)-receptor agonists MePhe(7)-neurokinin B and senktide in the isolated guinea pig lung. Exp Lung Res 36(9):509–521PubMedCrossRefGoogle Scholar
  46. Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, Patapoutian A (2010) Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330(6000):55–60Google Scholar
  47. Dai Y, Wang S, Tominaga M, Yamamoto S, Fukuoka T, Higashi T et al (2007) Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J Clin Invest 117(7):1979–1987PubMedPubMedCentralCrossRefGoogle Scholar
  48. Dean JB, Bayliss DA, Erickson JT, Lawing WL, Millhorn DE (1990) Depolarization and stimulation of neurons in nucleus tractus solitarii by carbon dioxide does not require chemical synaptic input. Neuroscience 36(1):207–216PubMedCrossRefGoogle Scholar
  49. Demediuk BH, Manning H, Lilly J, Fencl V, Weinberger SE, Weiss JW, Schwartzstein RM (1992) Dissociation between dyspnea and respiratory effort. Am Rev Respir Dis 146(5 Pt 1):1222–1225PubMedCrossRefGoogle Scholar
  50. Dey RD (2003) Controlling from within: neurophysiological plasticity of parasympathetic airway neurons. Am J Physiol Lung Cell Mol Physiol 284(4):L578–L580PubMedCrossRefGoogle Scholar
  51. Dicpinigaitis PV (2015) Clinical perspective - cough: an unmet need. Curr Opin Pharmacol 22:24–28PubMedCrossRefGoogle Scholar
  52. Driessen AK, Farrell MJ, Mazzone SB, McGovern AE (2015) The Role of the Paratrigeminal Nucleus in Vagal Afferent Evoked Respiratory Reflexes: A Neuroanatomical and Functional Study in Guinea Pigs. Front Physiol 6:378PubMedPubMedCentralCrossRefGoogle Scholar
  53. Du Kim Y, Lee SH, Lee SY, Seo JH, Kim JJ, Sa YJ, Park CB, Kim CK, Moon SW, Yim HW (2009) The effect of thoracosopic thoracic sympathetomy on pulmonary function and bronchial hyperresponsiveness. J Asthma 46(3):276–279PubMedCrossRefGoogle Scholar
  54. Elitt CM, McIlwrath SL, Lawson JJ, Malin SA, Molliver DC, Cornuet PK, Koerber HR, Davis BM, Albers KM (2006) Artemin overexpression in skin enhances expression of TRPV1 and TRPA1 in cutaneous sensory neurons and leads to behavioral sensitivity to heat and cold. J Neurosci 26(33):8578–8587PubMedCrossRefGoogle Scholar
  55. Evans KC, Banzett RB, Adams L, McKay L, Frackowiak RSJ, Corfield DR (2002) BOLD fMRI identifies limbic, paralimbic, and cerebellar activation during air hunger. J Neurophysiol 88(3):1500–1511PubMedGoogle Scholar
  56. Ezure K, Tanaka I (2006) Distribution and medullary projection of respiratory neurons in the dorsolateral pons of the rat. Neuroscience 141(2):1011–1023PubMedCrossRefGoogle Scholar
  57. Fabbretti E, Nistri A (2012) Regulation of P2X3 receptor structure and function. CNS Neurol Disord Drug Targets 11(6):687–698PubMedCrossRefGoogle Scholar
  58. Fahy JV, Wong HH, Geppetti P, Reis JM, Harris SC, Maclean DB, NADEL JA, Boushey HA (1995) Effect of an NK1 receptor antagonist (CP-99,994) on hypertonic saline-induced bronchoconstriction and cough in male asthmatic subjects. Am J Resp Crit Care Med 152(3):879–884PubMedCrossRefGoogle Scholar
  59. Fang D, Kong L-Y, Cai J, Li S, Liu X-D, Han J-S, Xing G-G (2015) Interleukin-6-mediated functional upregulation of TRPV1 receptors in dorsal root ganglion neurons through the activation of JAK/PI3K signaling pathway: roles in the development of bone cancer pain in a rat model. Pain 156(6):1124–1144PubMedGoogle Scholar
  60. Farrell MJ, Cole LJ, Chiapoco D, Egan GF, Mazzone SB (2012) Neural correlates coding stimulus level and perception of capsaicin-evoked urge-to-cough in humans. Neuroimage 61(4):1324–1335PubMedCrossRefGoogle Scholar
  61. Fischer A, McGregor GP, Saria A, Philippin B, Kummer W (1996a) Induction of tachykinin gene and peptide expression in guinea pig nodose primary afferent neurons by allergic airway inflammation. J Clin Invest 98(10):2284–2291PubMedPubMedCentralCrossRefGoogle Scholar
  62. Fischer A, Canning BJ, Undem BJ, Kummer W (1998) Evidence for an esophageal origin of VIP-IR and NO synthase-IR nerves innervating the guinea pig trachealis: a retrograde neuronal tracing and immunohistochemical analysis. J Comp Neurol 394(3):326–334PubMedCrossRefGoogle Scholar
  63. Fischer A, Mayer B, Kummer W (1996b) Nitric oxide synthase in vagal sensory and sympathetic neurons innervating the guinea-pig trachea. J Auton Nerv Syst 56(3):157–160PubMedCrossRefGoogle Scholar
  64. Fontana GA, Lavorini F (2006) Cough motor mechanisms. Respir Physiol Neurobiol 152(3):266–281PubMedCrossRefGoogle Scholar
  65. Ford AP (2012) In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization. Purinergic Signal 8(Suppl 1):3–26PubMedCrossRefGoogle Scholar
  66. Forsberg K, Karlsson JA, Theodorsson E, Lundberg JM, Persson CG (1988) Cough and bronchoconstriction mediated by capsaicin-sensitive sensory neurons in the guinea-pig. Pulm Pharmacol 1(1):33–39PubMedCrossRefGoogle Scholar
  67. Fredholm BB, Abbracchio MP, Burnstock G, Daly JW, Harden TK, Jacobson KA, Leff P, Williams M (1994) Nomenclature and classification of purinoceptors. Pharmacol Rev 46(2):143–156PubMedPubMedCentralGoogle Scholar
  68. Fryer AD, El-Fakahany EE (1990) Identification of three muscarinic receptor subtypes in rat lung using binding studies with selective antagonists. Life Sci 47(7):611–618PubMedCrossRefGoogle Scholar
  69. Fryer AD, Jacoby DB (1998) Muscarinic receptors and control of airway smooth muscle. An J Respir Crit Care Med158(5 Pt 3):S154-60Google Scholar
  70. Garssen J, Loveren H, Gierveld CM, Vliet H, Nijkamp FP (1993) Functional characterization of muscarinic receptors in murine airways. Br J Pharmacol 109(1):53–60PubMedPubMedCentralCrossRefGoogle Scholar
  71. Gavva NR, Treanor JJS, Garami A, Fang L, Surapaneni S, Akrami A, Alvarez F, Bak A, Darling M, Gore A, Jang GR, Kesslak JP, Ni L, Norman MH, Palluconi G, Rose MJ, Salfi M, Tan E, Romanovsky AA, Banfield C, Davar G (2008) Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136(1–2):202–210PubMedCrossRefGoogle Scholar
  72. Gerevich Z, Illes P (2004) P2Y receptors and pain transmission. Purinergic Signal 1(1):3–10PubMedPubMedCentralCrossRefGoogle Scholar
  73. Gibson RA, Robertson J, Mistry H, McCallum S, Fernando D, Wyres M, Yosipovitch G (2014) A randomised trial evaluating the effects of the TRPV1 antagonist SB705498 on pruritus induced by histamine, and cowhage challenge in healthy volunteers. PLoS ONE 9(7):e100610PubMedPubMedCentralCrossRefGoogle Scholar
  74. Gravenstein JS, Devloo RA, Beecher HK (1954) Effect of antitussive agents on experimental and pathological cough in man. J Appl Physiol 7(2):119–139PubMedGoogle Scholar
  75. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, Bacharier LB, Lemanske RF, Strunk RC Jr, Allen DB, Bloomberg GR, Heldt G, Krawiec M, Larsen G, Liu AH, Chinchilli VM, Sorkness CA, Taussig LM, Martinez FD (2006) Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 354(19):1985–1997PubMedCrossRefGoogle Scholar
  76. Hadziefendic S, Haxhiu MA (1999) CNS innervation of vagal preganglionic neurons controlling peripheral airways: a transneuronal labeling study using pseudorabies virus. J Auton Nerv Syst 76(2–3):135–145PubMedCrossRefGoogle Scholar
  77. Haggard P, Whitford B (2004) Supplementary motor area provides an efferent signal for sensory suppression. Brain Res Cogn Brain Res 19(1):52–58PubMedCrossRefGoogle Scholar
  78. Hale MW, Rook GAW, Lowry CA (2012) Pathways underlying afferent signaling of bronchopulmonary immune activation to the central nervous system. Chem Immunol Allergy 98:118–141PubMedCrossRefGoogle Scholar
  79. Haselton JR, Solomon IC, Motekaitis AM, Kaufman MP (1992) Bronchomotor vagal preganglionic cell bodies in the dog: an anatomic and functional study. J Appl Physiol 73(3):1122–1129PubMedGoogle Scholar
  80. Haxhiu MA, Jansen ASP, Cherniack NS, Loewy AD (1993) CNS innervation of airway-related parasympathetic preganglionic neurons: a transneuronal labeling study using pseudorabies virus. Brain Res 618(618, Issue 1):115–134PubMedCrossRefGoogle Scholar
  81. Haxhiu MA, Loewy AD (1996) Central connections of the motor and sensory vagal systems innervating the trachea. J Auton Nerv Syst 57(1–2):49–56PubMedCrossRefGoogle Scholar
  82. Hazari MS, Pan JH, Myers AC (2007) Nerve growth factor acutely potentiates synaptic transmission in vitro and induces dendritic growth in vivo on adult neurons in airway parasympathetic ganglia. Am J Physiol Lung Cell Mol Physiol 292(4):L992–L1001PubMedCrossRefGoogle Scholar
  83. Hewitt MM, Adams G, Mazzone SB Jr, Mori N, Yu L, Canning BJ (2016) Pharmacology of Bradykinin-Evoked Coughing in Guinea Pigs. J Pharmacol Exp Ther 357(3):620–628PubMedCrossRefGoogle Scholar
  84. Hinman A, Chuang H-H, Bautista DM, Julius D (2006) TRP channel activation by reversible covalent modification. Proc Natl Acad Sci U S A 103(51):19564–19568PubMedPubMedCentralCrossRefGoogle Scholar
  85. Holland C, van Drunen C, Denyer J, Smart K, Segboer C, Terreehorst I, Newlands A, Beerahee M, Fokkens W, Tsitoura DC (2014) Inhibition of capsaicin-driven nasal hyper-reactivity by SB-705498, a TRPV1 antagonist. Br J Clin Pharmacol 77(5):777–788PubMedPubMedCentralCrossRefGoogle Scholar
  86. Holtzman MJ, Sheller JR, Dimeo M, NADEL JA, Boushey HA (1980) Effect of ganglionic blockade on bronchial reactivity in atopic subjects. Am Rev Respir Dis 122(1):17–25PubMedGoogle Scholar
  87. Hoyle GW, Graham RM, Finkelstein JB, Nguyen KP, Gozal D, Friedman M (1998) Hyperinnervation of the airways in transgenic mice overexpressing nerve growth factor. Am J Respir Cell Mol Biol 18(2):149–157PubMedCrossRefGoogle Scholar
  88. Ikeda-Miyagawa Y, Kobayashi K, Yamanaka H, Okubo M, Wang S, Dai Y, Yagi H, Hirose M, Noguchi K (2015) Peripherally increased artemin is a key regulator of TRPA1/V1 expression in primary afferent neurons. Mol Pain 11:8PubMedPubMedCentralCrossRefGoogle Scholar
  89. Jammes Y, Mei N (1979) Assessment of the pulmonary origin of bronchoconstrictor vagal tone. J Physiol 291:305–316PubMedPubMedCentralCrossRefGoogle Scholar
  90. Jara-Oseguera A, Simon SA, Rosenbaum T (2008) TRPV1: on the road to pain relief. Curr Mol Pharmacol 1(3):255–269PubMedPubMedCentralCrossRefGoogle Scholar
  91. Joos GF, Germonpre PR, Kips JC, Peleman RA, Pauwels RA (1994) Sensory neuropeptides and the human lower airways: present state and future directions. Eur Respir J 7(6):1161–1171PubMedGoogle Scholar
  92. Kajekar R, Myers AC (2008) Calcitonin gene-related peptide affects synaptic and membrane properties of bronchial parasympathetic neurons. Respir Physiol Neurobiol 160(1):28–36PubMedCrossRefGoogle Scholar
  93. Kajekar R, Undem BJ, Myers AC (2003) Role of cyclooxygenase activation and prostaglandins in antigen-induced excitability changes of bronchial parasympathetic ganglia neurons. Am J Physiol Lung Cell Mol Physiol 284(4):L581–L587PubMedCrossRefGoogle Scholar
  94. Kalia M, Richter D (1985) Morphology of physiologically identified slowly adapting lung stretch receptor afferents stained with intra-axonal horseradish peroxidase in the nucleus of the tractus solitarius of the cat. I. A light microscopic analysis. J Comp Neurol 241(4):503–520PubMedCrossRefGoogle Scholar
  95. Kamei J, Takahashi Y, Yoshikawa Y, Saitoh A (2005) Involvement of P2X receptor subtypes in ATP-induced enhancement of the cough reflex sensitivity. Eur J Pharmacol 528(1–3):158–161PubMedCrossRefGoogle Scholar
  96. Karashima Y, Talavera K, Everaerts W, Janssens A, Kwan KY, Vennekens R, Nilius B, Voets T (2009) TRPA1 acts as a cold sensor in vitro and in vivo. Proc Natl Acad Sci U S A 106(4):1273–1278PubMedPubMedCentralCrossRefGoogle Scholar
  97. Karla W, Shams H, Orr JA, Scheid P (1992) Effects of the thromboxane A2 mimetic, U46,619, on pulmonary vagal afferents in the cat. Respir Physiol 87(3):383–396PubMedCrossRefGoogle Scholar
  98. Karlsson JA, Fuller RW (1999) Pharmacological regulation of the cough reflex--from experimental models to antitussive effects in Man. Pulm Pharmacol Ther 12(4):215–228PubMedCrossRefGoogle Scholar
  99. Kase Y, Kito G, Miyata T, Takahama K (1984) Influence of cerebral cortex stimulation upon cough-like spasmodic expiratory response (SER) and cough in the cat. Brain Res 306(1–2):293–298PubMedCrossRefGoogle Scholar
  100. Kavia RBC, Dasgupta R, Fowler CJ (2005) Functional imaging and the central control of the bladder. J Comp Neurol 493(1):27–32PubMedCrossRefGoogle Scholar
  101. Kawate T, Robertson JL, Li M, Silberberg SD, Swartz KJ (2011) Ion access pathway to the transmembrane pore in P2X receptor channels. J Gen Physiol 137(6):579–590PubMedPubMedCentralCrossRefGoogle Scholar
  102. Kc P, Mayer CA, Haxhiu MA (2004) Chemical profile of vagal preganglionic motor cells innervating the airways in ferrets: the absence of noncholinergic neurons. J Appl Physiol 97(4):1508–1517PubMedCrossRefGoogle Scholar
  103. Kelsen SG, Prestel TF, Cherniack NS, Chester EH, Deal EC (1981) Comparison of the respiratory responses to external resistive loading and bronchoconstriction. J Clin Invest 67(6):1761–1768PubMedPubMedCentralCrossRefGoogle Scholar
  104. Kerzel S, Path G, Nockher WA, Quarcoo D, Raap U, Groneberg DA, Dinh QT, Fischer A, Braun A, Renz H (2003) Pan-neurotrophin receptor p75 contributes to neuronal hyperreactivity and airway inflammation in a murine model of experimental asthma. Am J Respir Cell Mol Biol 28(2):170–178PubMedCrossRefGoogle Scholar
  105. Kesler BS, Canning BJ (1999) Regulation of baseline cholinergic tone in guinea-pig airway smooth muscle. J Physiol 518(Pt 3):843–855PubMedPubMedCentralCrossRefGoogle Scholar
  106. Khalid S, Murdoch R, Newlands A, Smart K, Kelsall A, Holt K, Dockry R, Woodcock A, Smith JA (2014) Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial. J Allergy Clin Immunol 134(1):56–62PubMedCrossRefGoogle Scholar
  107. Khansaheb M, Choi JY, Joo NS, Yang Y-M, Krouse M, Wine JJ (2011) Properties of substance P-stimulated mucus secretion from porcine tracheal submucosal glands. Am J Physiol Lung Cell Mol Physiol 300(3):L370–L379PubMedCrossRefGoogle Scholar
  108. Klassen KP, Morton DR, Curtis GM (1951) The clinical physiology of the human bronchi. III. The effect of vagus section on the cough reflex, bronchial caliber, and clearance of bronchial secretions. Surgery 29(4):483–490PubMedGoogle Scholar
  109. Koepp J, Lindsey CJ, Motta EM, Rae GA (2006) Role of the paratrigeminal nucleus in nocifensive responses of rats to chemical, thermal and mechanical stimuli applied to the hind paw. Pain 122(3):235–244PubMedCrossRefGoogle Scholar
  110. Kollarik M, Undem BJ (2006) Sensory transduction in cough-associated nerves. Respir Physiol Neurobiol 152(3):243–254PubMedCrossRefGoogle Scholar
  111. Krauhs JM (1984) Morphology of presumptive slowly adapting receptors in dog trachea. Anat Rec 210(1):73–85PubMedCrossRefGoogle Scholar
  112. Kubin L, Kimura H, Davies RO (1991) The medullary projections of afferent bronchopulmonary C fibres in the cat as shown by antidromic mapping. J Physiol 435:207–228PubMedPubMedCentralCrossRefGoogle Scholar
  113. Kummer W, Fischer A, Kurkowski R, Heym C (1992) The sensory and sympathetic innervation of guinea-pig lung and trachea as studied by retrograde neuronal tracing and double-labelling immunohistochemistry. Neuroscience 49(3):715–737PubMedCrossRefGoogle Scholar
  114. Kwong K, Kollarik M, Nassenstein C, Ru F, Undem BJ (2008) P2X2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating guinea pig lungs and esophagus. Am J Physiol Lung Cell Mol Physiol 295(5):L858–L865PubMedPubMedCentralCrossRefGoogle Scholar
  115. Lalloo UG, Fox AJ, Belvisi MG, Chung KF, Barnes PJ (1995) Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs. J Appl Physiol 79(4):1082–1087PubMedGoogle Scholar
  116. Lee LY, Pisarri TE (2001) Afferent properties and reflex functions of bronchopulmonary C-fibers. Respir Physiol 125(1–2):47–65PubMedCrossRefGoogle Scholar
  117. Lembrechts R, Pintelon I, Schnorbusch K, Timmermans JP, Adriaensen D, Brouns (2011) Expression of mechanogated two-pore domain potassium channels in mouse lungs: special reference to mechanosensory airway receptors. Histochem Cell Biol 136(4):371–385PubMedCrossRefGoogle Scholar
  118. Li A, Nattie EE (1997) Focal central chemoreceptor sensitivity in the RTN studied with a CO2 diffusion pipette in vivo. J Appl Physiol 83(2):420–428PubMedGoogle Scholar
  119. Lieu TM, Myers AC, Meeker S, Undem BJ (2012) TRPV1 induction in airway vagal low-threshold mechanosensory neurons by allergen challenge and neurotrophic factors. Am J Physiol Lung Cell Mol Physiol 302(9):L941–L948PubMedPubMedCentralCrossRefGoogle Scholar
  120. Liu Z, Hu Y, Yu X, Xi J, Fan X, Tse C-M, Myers AC, Pasricha PJ, Li X, Yu S (2015) Allergen challenge sensitizes TRPA1 in vagal sensory neurons and afferent C-fiber subtypes in guinea pig esophagus. Am J Physiol Gastrointest Liver Physiol 308(6):G482–G488PubMedPubMedCentralCrossRefGoogle Scholar
  121. Lotze M, Wietek B, Birbaumer N, Ehrhardt J, Grodd W, Enck P (2001) Cerebral activation during anal and rectal stimulation. Neuroimage 14(5):1027–1034PubMedCrossRefGoogle Scholar
  122. Luck JC (1970) Afferent vagal fibres with an expiratory discharge in the rabbit. J Physiol 211(1):63–71PubMedPubMedCentralCrossRefGoogle Scholar
  123. Lundberg JM, Alving K, Karlsson JA, Matran R, Nilsson G (1991) Sensory neuropeptide involvement in animal models of airway irritation and of allergen-evoked asthma. Am Rev Respir Dis 143(6):1429–1430, discussion 1430–1PubMedCrossRefGoogle Scholar
  124. Malin SA, Molliver DC, Koerber HR, Cornuet P, Frye R, Albers KM, Davis BM (2006) Glial cell line-derived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo. J Neurosci 26(33):8588–8599PubMedCrossRefGoogle Scholar
  125. Martling CR, Saria A, Fischer JA, Hokfelt T, Lundberg JM (1988) Calcitonin gene-related peptide and the lung: neuronal coexistence with substance P, release by capsaicin and vasodilatory effect. Regul Pept 20(2):125–139PubMedCrossRefGoogle Scholar
  126. Matsuzaki Y, Hamasaki Y, Said SI (1980) Vasoactive intestinal peptide: a possible transmitter of nonadrenergic relaxation of guinea pig airways. Science 210(4475):1252–1253PubMedCrossRefGoogle Scholar
  127. Mazzone SB, Canning BJ (2002) Synergistic interactions between airway afferent nerve subtypes mediating reflex bronchospasm in guinea pigs. Am J Physiol Gastrointest Liver Physiol 283(1):R86–R98Google Scholar
  128. Mazzone SB, McLennan L, McGovern AE, Egan GF, Farrell MJ (2007) Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging. Am J Respir Crit Care Med 176(4):327–332PubMedCrossRefGoogle Scholar
  129. McGovern AE, Davis-Poynter N, Yang S-K, Simmons DG, Farrell MJ, Mazzone SB (2015a) Evidence for multiple sensory circuits in the brain arising from the respiratory system: an anterograde viral tract tracing study in rodents. Brain Struct Funct 220(6):3683–3699PubMedCrossRefGoogle Scholar
  130. McGovern AE, Driessen AK, Simmons DG, Powell J, Davis-Poynter N, Farrell MJ, Mazzone SB (2015b) Distinct brainstem and forebrain circuits receiving tracheal sensory neuron inputs revealed using a novel conditional anterograde transsynaptic viral tracing system. J Neurosci 35(18):7041–7055PubMedCrossRefGoogle Scholar
  131. Meng J, Wang J, Steinhoff M, Dolly JO (2016) TNFalpha induces co-trafficking of TRPV1/TRPA1 in VAMP1-containing vesicles to the plasmalemma via Munc18-1/syntaxin1/SNAP-25 mediated fusion. Sci Rep 6:21226PubMedPubMedCentralCrossRefGoogle Scholar
  132. Meseguer V, Alpizar YA, Luis E, Tajada S, Denlinger B, Fajardo O, Manenschijn J-A, Fernandez-Pena C, Talavera A, Kichko T, Navia B, Sanchez A, Senaris R, Reeh P, Perez-Garcia MT, Lopez-Lopez JR, Voets T, Belmonte C, Talavera K, Viana F (2014) TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins. Nat Commun 5:3125PubMedPubMedCentralCrossRefGoogle Scholar
  133. Michel T, Theresine M, Poli A, Domingues O, Ammerlaan W, Brons NHC, Hentges F, Zimmer J (2011) Increased Th2 cytokine secretion, eosinophilic airway inflammation, and airway hyperresponsiveness in neurturin-deficient mice. J Immunol 186(11):6497–6504PubMedCrossRefGoogle Scholar
  134. Mills JE, Widdicombe JG (1970) Role of the vagus nerves in anaphylaxis and histamine-induced bronchoconstrictions in guinea-pigs. Br J Pharmacol 39(4):724–731PubMedPubMedCentralCrossRefGoogle Scholar
  135. Montell C, Rubin GM (1989) Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction. Neuron 2(4):1313–1323PubMedCrossRefGoogle Scholar
  136. Moran MM, Xu H, Clapham DE (2004) TRP ion channels in the nervous system. Curr Opinion Neurobiol 14(3):362–369CrossRefGoogle Scholar
  137. Muroi Y, Ru F, Chou Y-L, Carr MJ, Undem BJ, Canning BJ (2013) Selective inhibition of vagal afferent nerve pathways regulating cough using Nav 1.7 shRNA silencing in guinea pig nodose ganglia. Am J Physiol Gastrointest Liver Physiol 304(11):R1017–R1023Google Scholar
  138. Myers AC, Undem BJ, Weinreich D (1991) Influence of antigen on membrane properties of guinea pig bronchial ganglion neurons. J Appl Physiol 71(3):970–976PubMedGoogle Scholar
  139. Nassenstein C, Dawbarn D, Pollock K, Allen SJ, Erpenbeck VJ, Spies E, Krug N, Braun A (2006) Pulmonary distribution, regulation, and functional role of Trk receptors in a murine model of asthma. J Allergy Clin Immunol 118(3):597–605PubMedCrossRefGoogle Scholar
  140. Nassenstein C, Kammertoens T, Veres TZ, Uckert W, Spies E, Fuchs B, Krug N, Braun A (2007) Neuroimmune crosstalk in asthma: dual role of the neurotrophin receptor p75NTR. J Allergy Clin Immunol 120(5):1089–1096PubMedCrossRefGoogle Scholar
  141. Nassenstein C, Kwong K, Taylor-Clark T, Kollarik M, Macglashan DM, Braun A, Undem BJ (2008) Expression and function of the ion channel TRPA1 in vagal afferent nerves innervating mouse lungs. J Physiol 586(6):1595–1604PubMedPubMedCentralCrossRefGoogle Scholar
  142. Nassenstein C, Taylor-Clark TE, Myers AC, Ru F, Nandigama R, Bettner W, Undem BJ (2010) Phenotypic distinctions between neural crest and placodal derived vagal C-fibres in mouse lungs. J Physiol 588(Pt 23):4769–4783PubMedPubMedCentralCrossRefGoogle Scholar
  143. Nassini R, Materazzi S, Benemei S, Geppetti P (2014) The TRPA1 channel in inflammatory and neuropathic pain and migraine. Rev Physiol Biochem Pharmacol 167:1–43PubMedGoogle Scholar
  144. Nieber K, Baumgarten CR, Rathsack R, Furkert J, Oehme P, Kunkel G (1992) Substance P and beta-endorphin-like immunoreactivity in lavage fluids of subjects with and without allergic asthma. J Allergy Clin Immunol 90(4):646–652PubMedCrossRefGoogle Scholar
  145. Nishino T, Tagaito Y, Isono S (1996) Cough and other reflexes on irritation of airway mucosa in man. Pulm Pharmacol 9(5–6):285–292PubMedCrossRefGoogle Scholar
  146. North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82(4):1013–1067PubMedCrossRefGoogle Scholar
  147. Oh M-H, Oh SY, Lu J, Lou H, Myers AC, Zhu Z, Zheng T (2013) TRPA1-dependent pruritus in IL-13-induced chronic atopic dermatitis. J Immunol 191(11):5371–5382PubMedPubMedCentralCrossRefGoogle Scholar
  148. Oyamada Y, Ballantyne D, Muckenhoff K, Scheid P (1998) Respiration-modulated membrane potential and chemosensitivity of locus coeruleus neurones in the in vitro brainstem-spinal cord of the neonatal rat. J Physiol 513(Pt 2):381–398PubMedPubMedCentralCrossRefGoogle Scholar
  149. Pack AI, DeLaney RG (1983) Response of pulmonary rapidly adapting receptors during lung inflation. J Appl Physiol Respir Environ Exerc Physiol 55(3):955–963PubMedGoogle Scholar
  150. Pack RJ, Richardson PS (1984) The aminergic innervation of the human bronchus: a light and electron microscopic study. J Anat 138(Pt 3):493–502PubMedPubMedCentralGoogle Scholar
  151. Park CK, Bae JH, Kim HY, Jo HJ, Kim YH, Jung SJ, Kim JS, Oh SB (2010) Substance P sensitizes P2X3 in nociceptive trigeminal neurons. J Dent Res 89(10):1154–1159PubMedCrossRefGoogle Scholar
  152. Partanen M, Laitinen A, Hervonen A, Toivanen M, Laitinen LA (1982) Catecholamine- and acetylcholinesterase-containing nerves in human lower respiratory tract. Histochemistry 76(2):175–188PubMedCrossRefGoogle Scholar
  153. Path G, Braun A, Meents N, Kerzel S, Quarcoo D, Raap U, Hoyle GW, Nockher WA, Renz H (2002) Augmentation of allergic early-phase reaction by nerve growth factor. Am J Respir Crit Care Med 166(6):818–826PubMedCrossRefGoogle Scholar
  154. Pedersen SF, Owsianik G, Nilius B (2005) TRP channels: an overview. Cell Calcium 38(3–4):233–252PubMedCrossRefGoogle Scholar
  155. Peiffer C, Poline JB, Thivard L, Aubier M, Samson Y (2001) Neural substrates for the perception of acutely induced dyspnea. Am J Respir Crit Care Med 163(4):951–957PubMedCrossRefGoogle Scholar
  156. Pelleg A, Hurt CM (1996) Mechanism of action of ATP on canine pulmonary vagal C fibre nerve terminals. J Physiol 490(Pt 1):265–275PubMedPubMedCentralCrossRefGoogle Scholar
  157. Piedimonte G, Hegele RG, Auais A (2004) Persistent airway inflammation after resolution of respiratory syncytial virus infection in rats. Pediatric Res 55(4):657–665CrossRefGoogle Scholar
  158. Poliacek I, Jakus J, Simera M, Veternik M, Plevkova J (2014) Control of coughing by medullary raphe. Prog Brain Res 212:277–295PubMedCrossRefGoogle Scholar
  159. Ricco MM, Kummer W, Biglari B, Myers AC, Undem BJ (1996) Interganglionic segregation of distinct vagal afferent fibre phenotypes in guinea-pig airways. J Physiol 496(Pt 2):521–530PubMedPubMedCentralCrossRefGoogle Scholar
  160. Richardson CA, Herbert DA, Mitchell RA (1984) Modulation of pulmonary stretch receptors and airway resistance by parasympathetic efferents. J Appl Physiol Respir Environ Exerc Physiol 57(6):1842–1849PubMedGoogle Scholar
  161. Richerson GB (2004) Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci 5(6):449–461PubMedCrossRefGoogle Scholar
  162. Riera CE, Vogel H, Simon SA, Le Coutre J (2007) Artificial sweeteners and salts producing a metallic taste sensation activate TRPV1 receptors. Am J Physiol Gastrointest Liver Physiol 293(2):R626–R634Google Scholar
  163. Ruan T, Lin YS, Lin K-S, Kou YR (2005) Sensory transduction of pulmonary reactive oxygen species by capsaicin-sensitive vagal lung afferent fibres in rats. J Physiol 565(Pt 2):563–578PubMedPubMedCentralCrossRefGoogle Scholar
  164. Rybak IA, Shevtsova NA, Paton JFR, Dick TE, St-John WM, Morschel M, Dutschmann M (2004) Modeling the ponto-medullary respiratory network. Respir Physiol Neurobiol 143(2–3):307–319PubMedCrossRefGoogle Scholar
  165. Ryckmans T, Aubdool AA, Bodkin JV, Cox P, Brain SD, Dupont T, Fairman E, Hashizume Y, Ishii N, Kato T, Kitching L, Newman J, Omoto K, Rawson D, Strover J (2011) Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel. Bio Org Med Chem Letts 21(16):4857–4859CrossRefGoogle Scholar
  166. Salzer I, Gantumur E, Yousuf A, Boehm S (2016) Control of sensory neuron excitability by serotonin involves 5HT2C receptors and Ca(2+)-activated chloride channels. Neuropharmacology 110(Pt A):277–286PubMedCrossRefGoogle Scholar
  167. Sano M, Tsubone H, Sugano S (1992) Vagal afferent activities and respiratory reflexes during drug-induced bronchoconstriction in the guinea pig. J Vet Med Sci 54(5):989–998PubMedCrossRefGoogle Scholar
  168. Saper CB (2002) The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. Annu Rev Neurosci 25:433–469PubMedCrossRefGoogle Scholar
  169. Sarkar S, Hobson AR, Furlong PL, Woolf CJ, Thompson DG, Aziz Q (2001) Central neural mechanisms mediating human visceral hypersensitivity. Am J Physiol Gastrointest Liver Physiol 281(5):G1196–G1202PubMedGoogle Scholar
  170. Scano G, Stendardi L, Grazzini M (2005) Understanding dyspnoea by its language. Eur Respir J 25(2):380–385PubMedCrossRefGoogle Scholar
  171. Schelegle ES, Mansoor JK, Green JF (2000) Interaction of vagal lung afferents with inhalation of histamine aerosol in anesthetized dogs. Lung 178(1):41–52PubMedCrossRefGoogle Scholar
  172. Schelfhout V, van de Velde V, Maggi C, Pauwels R, Joos G (2009) The effect of the tachykinin NK(2) receptor antagonist MEN11420 (nepadutant) on neurokinin A-induced bronchoconstriction in asthmatics. Ther Adv Respir Dis 3(5):219–226PubMedCrossRefGoogle Scholar
  173. Segers LS, Shannon R, Lindsey BG (1985) Interactions between rostral pontine and ventral medullary respiratory neurons. J Neurophysiol 54(2):318–334PubMedGoogle Scholar
  174. Shannon R, Baekey DM, Morris KF, Li Z, Lindsey BG (2000) Functional connectivity among ventrolateral medullary respiratory neurones and responses during fictive cough in the cat. J Physiol 525(Pt 1):207–224PubMedPubMedCentralCrossRefGoogle Scholar
  175. Shannon R, Baekey DM, Morris KF, Lindsey BG (1998) Ventrolateral medullary respiratory network and a model of cough motor pattern generation. J Appl Physiol 84(6):2020–2035PubMedGoogle Scholar
  176. Shannon R, Baekey DM, Morris KF, Nuding SC, Segers LS, Lindsey BG (2004a) Pontine respiratory group neuron discharge is altered during fictive cough in the decerebrate cat. Respir Physiol Neurobiol 142(1):43–54PubMedCrossRefGoogle Scholar
  177. Shannon R, Baekey DM, Morris KF, Nuding SC, Segers LS, Lindsey BG (2004b) Production of reflex cough by brainstem respiratory networks. Pulm Pharmacol Ther 17(6):369–376PubMedCrossRefGoogle Scholar
  178. Shannon R, Zechman FW (1972) The reflex and mechanical response of the inspiratory muscles to an increased airflow resistance. Respir Physiol 16(1):51–69PubMedCrossRefGoogle Scholar
  179. Shibata T, Takahashi K, Matsubara Y, Inuzuka E, Nakashima F, Takahashi N, Kozai D, Mori Y, Uchida K (2016) Identification of a prostaglandin D2 metabolite as a neuritogenesis enhancer targeting the TRPV1 ion channel. Sci Rep 6:21261PubMedPubMedCentralCrossRefGoogle Scholar
  180. Smit LAM, Kogevinas M, Anto JM, Bouzigon E, Gonzalez JR, Le Moual N, Kromhout H, Carsin A-E, Pin I, Jarvis D, Vermeulen R, Janson C, Heinrich J, Gut I, Lathrop M, Valverde MA, Demenais F, Kauffmann F (2012) Transient receptor potential genes, smoking, occupational exposures and cough in adults. Resp Res 13:26CrossRefGoogle Scholar
  181. Smith CA, Rodman JR, Chenuel BJA, Henderson KS, Dempsey JA (2006) Response time and sensitivity of the ventilatory response to CO2 in unanesthetized intact dogs: central vs. peripheral chemoreceptors. J Appl Physiol 100(1):13–19PubMedCrossRefGoogle Scholar
  182. Smith JA, Aliverti A, Quaranta M, McGuinness K, Kelsall A, Earis J, Calverley PM (2012) Chest wall dynamics during voluntary and induced cough in healthy volunteers. J Physiol 590(3):563–574PubMedCrossRefGoogle Scholar
  183. Smith JC, Abdala APL, Koizumi H, Rybak IA, Paton JFR (2007) Spatial and functional architecture of the mammalian brain stem respiratory network: a hierarchy of three oscillatory mechanisms. J Neurophysiol 98(6):3370–3387PubMedPubMedCentralCrossRefGoogle Scholar
  184. Smith JC, Morrison DE, Ellenberger HH, Otto MR, Feldman JL (1989) Brainstem projections to the major respiratory neuron populations in the medulla of the cat. J Comp Neurol 281(1):69–96PubMedCrossRefGoogle Scholar
  185. Spaziano G, Luongo L, Guida F, Petrosino S, Matteis M, Palazzo E, Sullo N, de Novellis V, Di Marzo V, Rossi F, Maione S, D’Agostino B (2015) Exposure to Allergen Causes Changes in NTS Neural Activities after Intratracheal Capsaicin Application, in Endocannabinoid Levels and in the Glia Morphology of NTS. Biomed Res Int 2015:980983PubMedPubMedCentralCrossRefGoogle Scholar
  186. Stein AT, Ufret-Vincenty CA, Hua L, Santana LF, Gordon SE (2006) Phosphoinositide 3-kinase binds to TRPV1 and mediates NGF-stimulated TRPV1 trafficking to the plasma membrane. J Gen Physiol 128(5):509–522PubMedPubMedCentralCrossRefGoogle Scholar
  187. Struckmann N, Schwering S, Wiegand S, Gschnell A, Yamada M, Kummer W, Wess J, Haberberger RV (2003) Role of muscarinic receptor subtypes in the constriction of peripheral airways: studies on receptor-deficient mice. Mol Pharmacol 64(6):1444–1451PubMedCrossRefGoogle Scholar
  188. Szarek JL, Stewart NL, Spurlock B, Schneider C (1995) Sensory nerve- and neuropeptide-mediated relaxation responses in airways of Sprague–Dawley rats. J Appl Physiol (1985) 78(5):1679–1687Google Scholar
  189. Taguchi O, Kikuchi Y, Hida W, Iwase N, Satoh M, Chonan T, Takishima T (1991) Effects of bronchoconstriction and external resistive loading on the sensation of dyspnea. J Appl Physiol 71(6):2183–2190PubMedGoogle Scholar
  190. Talavera K, Gees M, Karashima Y, Meseguer VM, Vanoirbeek JAJ, Damann N, Everaerts W, Benoit M, Janssens A, Vennekens R, Viana F, Nemery B, Nilius B, Voets T (2009) Nicotine activates the chemosensory cation channel TRPA1. Nat Neurosci 12(10):1293–1299PubMedCrossRefGoogle Scholar
  191. Tatar M, Webber SE, Widdicombe JG (1988) Lung C-fibre receptor activation and defensive reflexes in anaesthetized cats. J Physiol 402:411–420PubMedPubMedCentralCrossRefGoogle Scholar
  192. Tominaga M, Wada M, Masu M (2001) Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia. Proc Natl Acad Sci U S A 98(12):6951–6956PubMedPubMedCentralCrossRefGoogle Scholar
  193. Trankner D, Hahne N, Sugino K, Hoon MA, Zuker C (2014) Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways. Proc Natl Acad Sci U S A 111(31):11515–11520PubMedPubMedCentralCrossRefGoogle Scholar
  194. Treede RD, Meyer RA, Raja SN, Campbell JN (1992) Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobiol 38(4):397–421PubMedCrossRefGoogle Scholar
  195. Uddman R, Sundler F, Emson P (1984) Occurrence and distribution of neuropeptide-Y-immunoreactive nerves in the respiratory tract and middle ear. Cell Tissue Res 237(2):321–327PubMedCrossRefGoogle Scholar
  196. Undem BJ, Chuaychoo B, Lee M-G, Weinreich D, Myers AC, Kollarik M (2004) Subtypes of vagal afferent C-fibres in guinea-pig lungs. J Physiol 556(Pt 3):905–917PubMedPubMedCentralCrossRefGoogle Scholar
  197. Vargas-Leal V, Bruno R, Derfuss T, Krumbholz M, Hohlfeld R, Meinl E (2005) Expression and function of glial cell line-derived neurotrophic factor family ligands and their receptors on human immune cells. J Immunol 175(4):2301–2308PubMedCrossRefGoogle Scholar
  198. Virchow JC, Julius P, Lommatzsch M, Luttmann W, Renz H, Braun A (1998) Neurotrophins are increased in bronchoalveolar lavage fluid after segmental allergen provocation. Am J Respir Crit Care Med 158(6):2002–2005PubMedCrossRefGoogle Scholar
  199. von Düring M, Andres KH (1988) Structure and functional anatomy of visceroreceptors in the mammalian respiratory system. Prog Brain Res 74:139–154CrossRefGoogle Scholar
  200. Wang S, Dai Y, Fukuoka T, Yamanaka H, Kobayashi K, Obata K, Cui X, Tominaga M, Noguchi K (2008) Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1: a molecular mechanism of inflammatory pain. Brain J Neurol 131(Pt 5):1241–1251Google Scholar
  201. Weigand LA, Ford AP, Undem BJ (2012) A role for ATP in bronchoconstriction-induced activation of guinea pig vagal intrapulmonary C-fibres. J Physiol 590(16):4109–4120PubMedPubMedCentralCrossRefGoogle Scholar
  202. Whicker SD, Armour CL, Black JL (1988) Responsiveness of bronchial smooth muscle from asthmatic patients to relaxant and contractile agonists. Pulm Pharmacol 1(1):25–31PubMedCrossRefGoogle Scholar
  203. Widdicombe JG (1954a) Receptors in the trachea and bronchi of the cat. J Physiol 123(1):71–104PubMedPubMedCentralCrossRefGoogle Scholar
  204. Widdicombe JG (1954b) Respiratory reflexes from the trachea and bronchi of the cat. J Physiol 123(1):55–70PubMedPubMedCentralCrossRefGoogle Scholar
  205. Widdicombe JG, NADEL JA (1963) Reflex effects of lung inflation on tracheal volume. J Appl Physiol 18:681–686PubMedGoogle Scholar
  206. Woolf CJ (2007) Central sensitization: uncovering the relation between pain and plasticity. Anesthesiology 106(4):864–867PubMedCrossRefGoogle Scholar
  207. Xu F, Frazier DT, Zhang Z, Baekey DM, Shannon R (1997) Cerebellar modulation of cough motor pattern in cats. J Appl Physiol 83(2):391–397PubMedGoogle Scholar
  208. Zaagsma J, Roffel AF, Meurs H (1997) Muscarinic control of airway function. Life Sci 60(13–14):1061–1068PubMedCrossRefGoogle Scholar
  209. Zaccone EJ, Lieu T, Muroi Y, Potenzieri C, Undem BE, Gao P, Han L, Canning BJ, Undem BJ (2016) Parainfluenza 3-Induced Cough Hypersensitivity in the Guinea Pig Airways. PLoS ONE 11(5):e0155526PubMedPubMedCentralCrossRefGoogle Scholar
  210. Zhang X, Huang J, McNaughton PA (2005) NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J 24(24):4211–4223PubMedPubMedCentralCrossRefGoogle Scholar
  211. Zhao M, Li Q, Tang J-S (2006) The effects of microinjection of morphine into thalamic nucleus submedius on formalin-evoked nociceptive responses of neurons in the rat spinal dorsal horn. Neurosci Lett 401(1–2):103–107PubMedCrossRefGoogle Scholar
  212. Zhu W, Dey RD (2001) Projections and pathways of VIP- and nNOS-containing airway neurons in ferret trachea. Am J Respir Cell Mol Biol 24(1):38–43PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Katrin Julia Audrit
    • 1
    • 2
  • Lucas Delventhal
    • 1
    • 2
  • Öznur Aydin
    • 1
    • 2
  • Christina Nassenstein
    • 1
    • 2
    Email author
  1. 1.Institute of Anatomy and Cell BiologyGiessenGermany
  2. 2.German Center for Lung Research (DZL)GiessenGermany

Personalised recommendations