Skip to main content
Thorax logoLink to Thorax
. 2004 Sep;59(9):769–772. doi: 10.1136/thx.2003.012930

Antitussive activity of iodo-resiniferatoxin in guinea pigs

M Trevisani 1, A Milan 1, R Gatti 1, A Zanasi 1, S Harrison 1, G Fontana 1, A Morice 1, P Geppetti 1
PMCID: PMC1747129  PMID: 15333853

Abstract

Background: Iodo-resiniferatoxin (I-RTX) has recently been described as an ultra potent antagonist of the transient receptor potential vanilloid-1 (TRPV1).

Methods: The ability of I-RTX to inhibit cough induced by inhalation of two putative TRPV1 stimulants (capsaicin and citric acid) was tested in non-anaesthetised guinea pigs.

Results: Pretreatment with I-RTX either intraperitoneally (0.03–0.3 µmol/kg) or by aerosol (0.1–3 µM) reduced the number of coughs produced by inhalation of citric acid (0.25 M) and capsaicin (30 µM) in a dose dependent manner. Capsazepine (CPZ) also reduced citric acid and capsaicin induced cough, but the activity of I-RTX was 10–100 times more potent than CPZ in all the experimental conditions tested.

Conclusions: I-RTX is a novel and potent antitussive drug which inhibits cough mediated by agents possibly acting via TRPV1 activation.

Full Text

The Full Text of this article is available as a PDF (113.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Benham C. D., Davis J. B., Randall A. D. Vanilloid and TRP channels: a family of lipid-gated cation channels. Neuropharmacology. 2002 Jun;42(7):873–888. doi: 10.1016/s0028-3908(02)00047-3. [DOI] [PubMed] [Google Scholar]
  2. Bevan S., Geppetti P. Protons: small stimulants of capsaicin-sensitive sensory nerves. Trends Neurosci. 1994 Dec;17(12):509–512. doi: 10.1016/0166-2236(94)90149-x. [DOI] [PubMed] [Google Scholar]
  3. Bonini S., Lambiase A., Lapucci G., Properzi F., Bresciani M., Bracci Laudiero M. L., Mancini M. J., Procoli A., Micera A., Sacerdoti G. Nerve growth factor and asthma. Allergy. 2002;57 (Suppl 72):13–15. doi: 10.1034/j.1398-9995.57.s72.3.x. [DOI] [PubMed] [Google Scholar]
  4. Caterina M. J., Schumacher M. A., Tominaga M., Rosen T. A., Levine J. D., Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997 Oct 23;389(6653):816–824. doi: 10.1038/39807. [DOI] [PubMed] [Google Scholar]
  5. Chen C. C., England S., Akopian A. N., Wood J. N. A sensory neuron-specific, proton-gated ion channel. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10240–10245. doi: 10.1073/pnas.95.17.10240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chuang H. H., Prescott E. D., Kong H., Shields S., Jordt S. E., Basbaum A. I., Chao M. V., Julius D. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature. 2001 Jun 21;411(6840):957–962. doi: 10.1038/35082088. [DOI] [PubMed] [Google Scholar]
  7. Doherty M. J., Mister R., Pearson M. G., Calverley P. M. Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease. Thorax. 2000 Aug;55(8):643–649. doi: 10.1136/thorax.55.8.643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Forsberg K., Karlsson J. A. Cough induced by stimulation of capsaicin-sensitive sensory neurons in conscious guinea-pigs. Acta Physiol Scand. 1986 Oct;128(2):319–320. doi: 10.1111/j.1748-1716.1986.tb07981.x. [DOI] [PubMed] [Google Scholar]
  9. Gunthorpe Martin J., Benham Christopher D., Randall Andrew, Davis John B. The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Pharmacol Sci. 2002 Apr;23(4):183–191. doi: 10.1016/s0165-6147(02)01999-5. [DOI] [PubMed] [Google Scholar]
  10. Huang Susan M., Bisogno Tiziana, Trevisani Marcello, Al-Hayani Abdulmonem, De Petrocellis Luciano, Fezza Filomena, Tognetto Michele, Petros Timothy J., Krey Jocelyn F., Chu Constance J. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8400–8405. doi: 10.1073/pnas.122196999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hwang S. W., Cho H., Kwak J., Lee S. Y., Kang C. J., Jung J., Cho S., Min K. H., Suh Y. G., Kim D. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6155–6160. doi: 10.1073/pnas.97.11.6155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kastelik Jack A., Thompson Rachel H., Aziz Imran, Ojoo Josephine C., Redington Anthony E., Morice Alyn H. Sex-related differences in cough reflex sensitivity in patients with chronic cough. Am J Respir Crit Care Med. 2002 Oct 1;166(7):961–964. doi: 10.1164/rccm.2109061. [DOI] [PubMed] [Google Scholar]
  13. Kollarik Marian, Undem Bradley J. Mechanisms of acid-induced activation of airway afferent nerve fibres in guinea-pig. J Physiol. 2002 Sep 1;543(Pt 2):591–600. doi: 10.1113/jphysiol.2002.022848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lalloo U. G., Fox A. J., Belvisi M. G., Chung K. F., Barnes P. J. Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs. J Appl Physiol (1985) 1995 Oct;79(4):1082–1087. doi: 10.1152/jappl.1995.79.4.1082. [DOI] [PubMed] [Google Scholar]
  15. Maggi C. A., Bevan S., Walpole C. S., Rang H. P., Giuliani S. A comparison of capsazepine and ruthenium red as capsaicin antagonists in the rat isolated urinary bladder and vas deferens. Br J Pharmacol. 1993 Mar;108(3):801–805. doi: 10.1111/j.1476-5381.1993.tb12881.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Midgren B., Hansson L., Karlsson J. A., Simonsson B. G., Persson C. G. Capsaicin-induced cough in humans. Am Rev Respir Dis. 1992 Aug;146(2):347–351. doi: 10.1164/ajrccm/146.2.347. [DOI] [PubMed] [Google Scholar]
  17. Morice A. H., Kastelik J. A., Thompson R. Cough challenge in the assessment of cough reflex. Br J Clin Pharmacol. 2001 Oct;52(4):365–375. doi: 10.1046/j.0306-5251.2001.01475.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. O'Connell F., Thomas V. E., Pride N. B., Fuller R. W. Capsaicin cough sensitivity decreases with successful treatment of chronic cough. Am J Respir Crit Care Med. 1994 Aug;150(2):374–380. doi: 10.1164/ajrccm.150.2.8049818. [DOI] [PubMed] [Google Scholar]
  19. Premkumar L. S., Ahern G. P. Induction of vanilloid receptor channel activity by protein kinase C. Nature. 2000 Dec 21;408(6815):985–990. doi: 10.1038/35050121. [DOI] [PubMed] [Google Scholar]
  20. Rigoni Michela, Trevisani Marcello, Gazzieri David, Nadaletto Riccardo, Tognetto Michele, Creminon Christophe, Davis John B., Campi Barbara, Amadesi Silvia, Geppetti Pierangelo. Neurogenic responses mediated by vanilloid receptor-1 (TRPV1) are blocked by the high affinity antagonist, iodo-resiniferatoxin. Br J Pharmacol. 2003 Mar;138(5):977–985. doi: 10.1038/sj.bjp.0705110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sanchez J. F., Krause J. E., Cortright D. N. The distribution and regulation of vanilloid receptor VR1 and VR1 5' splice variant RNA expression in rat. Neuroscience. 2001;107(3):373–381. doi: 10.1016/s0306-4522(01)00373-6. [DOI] [PubMed] [Google Scholar]
  22. Seabrook Guy R., Sutton Kathy G., Jarolimek Wolfgang, Hollingworth Gregory J., Teague Simon, Webb Janine, Clark Natalie, Boyce Susan, Kerby Julie, Ali Zahid. Functional properties of the high-affinity TRPV1 (VR1) vanilloid receptor antagonist (4-hydroxy-5-iodo-3-methoxyphenylacetate ester) iodo-resiniferatoxin. J Pharmacol Exp Ther. 2002 Dec;303(3):1052–1060. doi: 10.1124/jpet.102.040394. [DOI] [PubMed] [Google Scholar]
  23. Szallasi A., Blumberg P. M. Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol Rev. 1999 Jun;51(2):159–212. [PubMed] [Google Scholar]
  24. Szallasi A. The vanilloid (capsaicin) receptor: receptor types and species differences. Gen Pharmacol. 1994 Mar;25(2):223–243. doi: 10.1016/0306-3623(94)90049-3. [DOI] [PubMed] [Google Scholar]
  25. Tominaga M., Caterina M. J., Malmberg A. B., Rosen T. A., Gilbert H., Skinner K., Raumann B. E., Basbaum A. I., Julius D. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 1998 Sep;21(3):531–543. doi: 10.1016/s0896-6273(00)80564-4. [DOI] [PubMed] [Google Scholar]
  26. Wahl P., Foged C., Tullin S., Thomsen C. Iodo-resiniferatoxin, a new potent vanilloid receptor antagonist. Mol Pharmacol. 2001 Jan;59(1):9–15. doi: 10.1124/mol.59.1.9. [DOI] [PubMed] [Google Scholar]
  27. Widdicombe J. G. Afferent receptors in the airways and cough. Respir Physiol. 1998 Oct;114(1):5–15. doi: 10.1016/s0034-5687(98)00076-0. [DOI] [PubMed] [Google Scholar]
  28. Wong C. H., Morice A. H. Cough threshold in patients with chronic obstructive pulmonary disease. Thorax. 1999 Jan;54(1):62–64. doi: 10.1136/thx.54.1.62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Xue Q., Yu Y., Trilk S. L., Jong B. E., Schumacher M. A. The genomic organization of the gene encoding the vanilloid receptor: evidence for multiple splice variants. Genomics. 2001 Aug;76(1-3):14–20. doi: 10.1006/geno.2001.6582. [DOI] [PubMed] [Google Scholar]
  30. Zygmunt P. M., Petersson J., Andersson D. A., Chuang H., Sørgård M., Di Marzo V., Julius D., Högestätt E. D. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999 Jul 29;400(6743):452–457. doi: 10.1038/22761. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES