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TRP Channel Antagonists as Potential Antitussives

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Abstract

Cough is a troublesome symptom associated with many respiratory diseases. In some instances cough can become prolonged and excessive, and chronic cough of various aetiologies is a common presentation to specialist respiratory clinics. However, current treatment options are limited. Despite its importance, our understanding of the mechanisms that provoke cough is poor. Recent investigation has focused on the interaction between G-protein-coupled receptors and ion channels expressed on airway sensory nerves that are responsible for driving the cough reflex. In particular, the Transient Receptor Potential class of ion channels appears to play a major role as a regulator of the afferent arm of the cough reflex and could be involved in the heightened cough response observed in disease states. Current research investigating the pathogenesis of cough supports the development of TRP channel inhibitors as novel and selective treatment modalities.

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References

  1. McCormick A, Fleming D, Charlton J (1995) Office of population censuses and surveys. In: Morbidity statistics from general practice, fourth national study 1991–1992, series MB5 no. 3. HMSO, London

  2. Ford A, Forman D, Moayyedi P, Morice A (2006) Cough in the community: a cross sectional survey and the relationship to gastrointestinal symptoms. Thorax 61:975–979

    Article  PubMed  CAS  Google Scholar 

  3. World Health Organisation (2007) Global surveillance, prevention and control of chronic respiratory disease: a comprehensive approach. WHO Press, Geneva

    Google Scholar 

  4. World Health Organisation (2011) Fact sheet no. 307: asthma. http://www.who.int/mediacentre/factsheets/fs307/en/index.html. Accessed 22 Sept 2011

  5. World Health Organisation (2011) Fact sheet no. 315: chronic obstructive pulmonary disease (COPD). http://www.who.int/mediacentre/factsheets/fs315/en/index.html. Accessed 22 Sept 2011

  6. Hay AD, Heron J, Ness A (2005) The prevalence of symptoms and consultations in pre-school children in the Avon Longitudinal Study of Parents and Children (ALSPAC): a prospective cohort study. Fam Pract 22(4):367–374

    Article  PubMed  Google Scholar 

  7. Sands R, Shanmugavadivel D, Stephenson T, Wood D (2011) Medical problems presenting to paediatric emergency departments: 10 years on. Emerg Med J. doi:10.1136/emj.2010.106229

  8. American Academy of Paediatrics (1997) Committee on drugs use of codeine- and dextromethorphan-containing cough remedies in children. Paediatrics 99:918–920

    Article  Google Scholar 

  9. Gunn V, Taha S, Liebelt E, Serwint J (2001) Toxicity of over-the-counter cough and cold medications. Pediatrics 108:E52

    Article  PubMed  CAS  Google Scholar 

  10. Centers for Disease Control (2007) Infant deaths associated with cough and cold medications—two states, 2005. Morb Mortal Wkly Rep 56:1–4

    Google Scholar 

  11. Vassilev Z, Chu A, Ruk B, Adams E, Marcus S (2009) Adverse reactions to over-the-counter cough and cold products among children: the cases managed out of hospitals. J Clin Pharm Ther 34:313–318

    Article  PubMed  CAS  Google Scholar 

  12. US Food and Drug Administration (2008) Public Health Advisory: FDA recommends that over-the-counter cough and cold products not be used for infants and children under 2 years of age. http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm051137.html. Accessed 7 Sep 2009

  13. Karlsson J, Fuller R (1999) Pharmacological regulation of the cough reflex—from experimental models to antitussive effects in man. Pulm Pharmacol Ther 12:215–228

    Article  PubMed  CAS  Google Scholar 

  14. Belvisi MG, Geppetti P (2004) Cough 7: current and future drugs for the treatment of chronic cough. Thorax 59:438–440

    Article  PubMed  CAS  Google Scholar 

  15. Reynolds SM, Mackenzie AJ, Spina D, Page CP (2004) The pharmacology of cough. Trends Pharmacol Sci 25:569–576

    Article  PubMed  CAS  Google Scholar 

  16. Canning B, Mori N, Mazzone S (2006) Vagal afferent nerves regulating the cough reflex. Respir Physiol Neurobiol 152:223–242

    Article  PubMed  Google Scholar 

  17. Nasra J, Belvisi MG (2009) Modulation of sensory nerve function and the cough reflex: understanding disease pathogenesis. Pharmacol Ther 124(3):354–375

    Article  PubMed  CAS  Google Scholar 

  18. Birrell MA, Belvisi MG, Grace MS, Sasofsky L, Farqui S, Hele D, Maher S, Freund-Michel V, Morice A (2009) TRPA1 agonists evoke coughing in guinea pig and human volunteers. Am J Respir Crit Care Med 180:1042–1047

    Article  PubMed  CAS  Google Scholar 

  19. Andre E, Gatti R, Trevisani M, Preti D, Baraldi P, Patacchini R, Geppetti P (2009) Transient receptor potential ankyrin receptor 1 is a novel target for pro-tussive agents. Br J Pharmacol 158:1621–1628

    Article  PubMed  CAS  Google Scholar 

  20. Lalloo U, Fox A, Belvisi MG, Chung F (1995) Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs. J Appl Physiol 79:1082–1087

    PubMed  CAS  Google Scholar 

  21. Groneberg D, Niimi A, Dinh Q, Cosio B, Hew M, Fischer A, Chung K (2004) Increased expression of Transient Receptor Potential Vanilloid-1 in airway nerves of chronic cough. Am J Respir Crit Care Med 170:1276–1280

    Article  PubMed  Google Scholar 

  22. Caterina M, Schumacher M, Tominaga M, Rosen T, Levine J, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824

    Article  PubMed  CAS  Google Scholar 

  23. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Søgard M, Di Marzo V, Julius D, Högestätt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457

    Article  PubMed  CAS  Google Scholar 

  24. Grace MS, Birrell MA, Dubuis E, Belvisi MG (2011) Tobacco smoke induced cough: mechanisms driving acute and chronic cough pathology. In: Moldoveanu AM (ed) Advanced topics in environmental health and air pollution case studies. InTech Open Access Publisher, Rijeka

    Google Scholar 

  25. Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim D, Oh U (2000) Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci USA 97:6155–6160

    Article  PubMed  CAS  Google Scholar 

  26. Jordt SE, Bautista DM, Chuang H, McKemy DD, Zygmunt PM, Högestätt ED, Meng ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265

    Article  PubMed  CAS  Google Scholar 

  27. Bautista DM, Movahed P, Hinman A, Axelsson HE, Sterner O, Högestätt ED, Julius D, Jordt SE, Zygmunt PM (2005) Pungent products from garlic activated the sensory ion channel TRPA1. Proc Natl Acad Sci USA 102:12248–12252

    Article  PubMed  CAS  Google Scholar 

  28. Bautista D, Jordt S, Nikai T, Tsuruda P, Read A, Poblete J, Yamoah E, Basbaum A, Julius D (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124:1269–1282

    Article  PubMed  CAS  Google Scholar 

  29. Bandell M, Story GM, Hwang SW et al (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41:849–857

    Article  PubMed  CAS  Google Scholar 

  30. Macpherson LJ, Geierstanger BH, Viswanath V et al (2005) The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr Biol 15:929–934

    Article  PubMed  CAS  Google Scholar 

  31. Facchinetti F, Amadei F, Geppetti P et al (2007) Alpha, beta-unsaturated aldehydes in cigarette smoke release inflammatory mediators from human macrophages. Am J Respir Cell Mol Biol 37:617–623

    Article  PubMed  CAS  Google Scholar 

  32. Macpherson LJ, Dubin AE, Evans MJ et al (2007) Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445:541–545

    Article  PubMed  CAS  Google Scholar 

  33. McNamara CR, Mandel-Brehm J, Bautista DM et al (2007) TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci USA 104:13525–13530

    Article  PubMed  CAS  Google Scholar 

  34. Trevisani M, Siemens J, Materazz S et al (2007) 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci USA 104:13519–13524

    Article  PubMed  CAS  Google Scholar 

  35. Andrè E, Campi B, Materazzi S et al (2008) Cigarette smoke-induced neurogenic inflammation is mediated by alpha, beta-unsaturated aldehydes and the TRPA1 receptor in rodents. J Clin Investig 118:2574–2582

    PubMed  Google Scholar 

  36. Brône B, Peeters PJ, Marrannes R et al (2008) Tear gasses CN, CR, and CS are potent activators of the human TRPA1 receptor. Toxicol Appl Pharmacol 231:150–156

    Article  PubMed  Google Scholar 

  37. Andersson DA, Gentry C, Moss S et al (2008) Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci 28:2485–2494

    Article  PubMed  CAS  Google Scholar 

  38. Niimi A, Chung KF (2004) Airway inflammation and remodelling changes in patients with chronic cough: Do they tell us about the cause of cough? Pulm Pharmacol Ther 17:441–446

    Article  PubMed  CAS  Google Scholar 

  39. Klink ME, Dodge R, Quan SF (1994) The relation of sleep complaints to respiratory symptoms in a general population. Chest 105:151–154

    Article  PubMed  CAS  Google Scholar 

  40. Everett CF, Kastelik JA, Thompson RH, Morice AH (2007) Chronic persistent cough in the community: a questionnaire survey. Cough 3:5

    Article  PubMed  Google Scholar 

  41. Browne WJ, Wood CJ, Desai M, Weller PH (2009) Urinary incontinence in 9–16 year olds with cystic fibrosis compared to other respiratory conditions and a normal group. J Cyst Fibros 8:50–57

    Article  PubMed  CAS  Google Scholar 

  42. Morice A, Fontana G, Belvisi MG, Birring S, Chung KF, Dicpinigaitis P, Kastelik J, McGarvey L, Smith J, Tatar M, Widdicombe J (2007) ERS guidelines on the assessment of cough. Eur Respir J 29:1256–1276

    Article  PubMed  CAS  Google Scholar 

  43. Maher SA, Birrell MA, Belvisi MG (2009) Prostaglandin E2 mediates cough via the EP3 reeptor: implications for future disease therapy. Am J Respir Crit Care Med 180:923–928

    Article  PubMed  CAS  Google Scholar 

  44. Fox A, Lalloo U, Belvisi M, Bernareggi M, Chung KF, Barnes P (1996) Bradykinin evoked sensitisation of airway sensory nerves: a mechanism for ACE-inhibitor cough. Nat Med 2:814–817

    Article  PubMed  CAS  Google Scholar 

  45. Grace MS, Birrell MA, Maher SA, Belvisi MG (2011) TRPA1 and TRPV1 mediate tussive responses to PGE2, bradykinin and low pH. Am J Respir Crit Care Med 183:A5543

    Google Scholar 

  46. Choudry N, Fuller R, Pride N (1989) Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin and histamine. Am Rev Respir Dis 140:137–141

    Article  PubMed  CAS  Google Scholar 

  47. Ho C, Gu Q, Hong J, Lee L (2000) Prostaglandin (E2) enhances chemical and mechanical sensitivities of pulmonary C fibres in the rat. Am J Respir Crit Care Med 162:528–533

    PubMed  CAS  Google Scholar 

  48. Kwong K, Lee LY (2002) PGE(2) sensitizes cultured pulmonary vagal sensory neurons to chemical and electrical stimuli. J Appl Physiol 93(4):1419–1428

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  50. Minke B (2001) The TRP channel and phospholipase C-mediated signaling. Cell Mol Neurobiol 21:629–643

    Article  PubMed  CAS  Google Scholar 

  51. 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 sensitisation of TRPA1: a molecular mechanism of inflammatory pain. Brain 131:1241–1251

    Article  PubMed  Google Scholar 

  52. Chuang H, Prescott ED, Kong H, Shields S, Jordt S-E, Basbaum AI, Chao MV, Julius D (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4, 5)P2-mediated inhibition. Nature 411:957–962

    Article  PubMed  CAS  Google Scholar 

  53. Woo DH, Jung SJ, Zhu MH, Park CK, Kim YH, Oh SB, Lee CJ (2008) Direct activation of Transient Receptor Potential Vanilloid 1 (TRPV1) by diacylglycerol (DAG). Mol Pain 4:42

    Article  PubMed  Google Scholar 

  54. Vellani V, Mapplebeck S, Moriondo A, Davis JB, McNaughton PA (2001) Protein kinase C activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide. J Physiol 534:813–825

    Article  PubMed  CAS  Google Scholar 

  55. Bessac BF, Jordt SE (2008) Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control. Physiology (Bethesda) 23:360–370

    Article  CAS  Google Scholar 

  56. Gunthorpe MJ, Chizh BA (2009) Clinical development of TRPV1 antagonists: targeting a pivotal point in the pain pathway. Drug Discov Today 14:56–67

    Article  PubMed  CAS  Google Scholar 

  57. Trevisani M, Milan A, Gatti R, Zanasi A, Harrison S, Fontana G, Morice A, Geppetti P (2004) Antitussive activity of iodo-resiniferatoxin in guinea pigs. Thorax 59:769–772

    Article  PubMed  CAS  Google Scholar 

  58. Lehto S, Tamir R, Deng H, Klionsky L, Kuang R, Le A, Lee D, Louis J, Magal E, Manning B, Rubino J, Surapaneni S, Tamayo N, Wang T, Wang J, Wang J, Wang W, Youngblood B, Zhang M, Zhu D, Norman M, Gavva N (2008) Antihyperalgesic effects of (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)-acrylamide (AMG8562), a novel Transient Receptor Potential Vanilloid Type 1 modulator that does not cause hyperthermia in rats. J Pharmacol Exp Ther 326:218–229

    Article  PubMed  CAS  Google Scholar 

  59. Viana F, Ferrer-Montiel A (2009) TRPA1 modulators in preclinical development. Expert Opin Ther Patients 19:1788–1799

    Google Scholar 

  60. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, Patapoutian A (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–829

    Article  PubMed  CAS  Google Scholar 

  61. Zurborg S, Yurgionas B, Jira J, Caspani O, Heppenstall P (2007) Direct activation of the ion channel TRPA1 by Ca2+. Nat Neurosci 10:277–279

    Article  PubMed  CAS  Google Scholar 

  62. Cavanaugh E, Simkin D, Kim D (2008) Activation of transient receptor potential A1 channels by mustard oil, tetrahydrocannabinol and Ca2+ reveals different functional channel states. Neuroscience 154:1467–1476

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

MAB and MG were funded by project grants from the Medical Research Council (MRC, UK) (MAB, G0800196; MG, G0800195). ED was funded by a grant from the Wellcome Trust (089301/Z/09/Z).

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Correspondence to Maria G. Belvisi.

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Grace, M.S., Dubuis, E., Birrell, M.A. et al. TRP Channel Antagonists as Potential Antitussives. Lung 190, 11–15 (2012). https://doi.org/10.1007/s00408-011-9322-3

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