, Volume 186, Supplement 1, pp 66–69 | Cite as

Preclinical Assessment of Novel Therapeutics on the Cough Reflex: Cannabinoid Agonists as Potential Antitussives

  • Maria G. BelvisiEmail author


Cough, a reflex defense mechanism, is a common symptom of many airway inflammatory diseases. At present there are no satisfactory treatments for cough that have an acceptable side effect profile. Recent data have described the inhibitory effect of selective cannabinoid CB2 receptor agonists on sensory nerve activity in vitro and the cough reflex in a guinea pig model. CB2 receptor expression is limited in the central nervous system (CNS) and hence the development of selective agonists may provide a new therapeutic strategy for treatment of cough devoid of the CNS-mediated side effects that are normally associated with nonselective cannabinoid agonists.


Cannabinoids Cough Sensory nerves 


  1. 1.
    Widdicombe JG (1999) Advances in understanding and treatment of cough. Monaldi Arch Chest Dis 54:275–279PubMedGoogle Scholar
  2. 2.
    Shroeder K, Fahey T (2002) Systematic review of randomised controlled trials of over the counter cough medicines for acute cough in adults. BMJ 324:1–6Google Scholar
  3. 3.
    Karlsson JA, Fuller RW (1999) Pharmacological regulation of the cough reflex – from experimental models to antitussive effects in man. Pulm Pharmacol Ther 12:215–228PubMedCrossRefGoogle Scholar
  4. 4.
    Moreaux B, Beerens D, Gustin P (1999) Development of a cough induction test in pigs: effects of SR 48968 and enalapril. J Vet Pharmacol Ther 22:387–389PubMedCrossRefGoogle Scholar
  5. 5.
    Forsberg K, Karlsson JA, Theodorsen E, Lundberg JM, Persson CGA (1988) Cough and bronchoconstriction mediated by capsaicin-sensitive sensory neurons in guinea pigs. Pulm Pharmacol 1:33–39PubMedCrossRefGoogle Scholar
  6. 6.
    Fox AJ, Barnes PJ, Urban L, Dray A (1993) An in vivo study of the properties of single vagal afferents innervating guinea pig airways. J Physiol 469:21–35PubMedGoogle Scholar
  7. 7.
    Fox AJ (1996) Modulation of cough and airway sensory fibres. Pulm Pharmacol 9:335–342PubMedCrossRefGoogle Scholar
  8. 8.
    Fox AJ, Lalloo UG, Belvisi MG, Bernareggi M, Chung KF, Barnes PJ (1996) Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough. Nat Med 2:814–817PubMedCrossRefGoogle Scholar
  9. 9.
    Fox AJ, Barnes PJ, Venkatesan P, Belvisi MG (1997) Activation of large conductance potassium channels inhibits the afferent and efferent function of airway sensory nerves in the guinea pig. J Clin Invest 99:513–519PubMedCrossRefGoogle Scholar
  10. 10.
    Lalloo UG, Fox AJ, Belvisi M, Chung K, Barnes PJ (1995) Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs. J Appl Physiol 79:1082–1087PubMedGoogle Scholar
  11. 11.
    Trevisani M, Milan A, Gatti R, Zanasi A, Harrison S, Fontana G, Morice AH, Geppetti P (2004) Antitussive activity of iodo-resiniferatoxin in guinea pigs. Thorax 59(9):769–772PubMedCrossRefGoogle Scholar
  12. 12.
    Liu Q, Fujimura M, Tachibana H, Myou S, Kasahara K, Yasui M (2001) Characterization of increased cough sensitivity after antigen challenge in guinea pigs. Clin Exp Allergy 31(3):474–484PubMedCrossRefGoogle Scholar
  13. 13.
    Oribe Y, Fujimura M, Kita T, Katayama N, Nishitsuji M, Hara J, Myou S, Nakao S (2005) Attenuating effect of H+K+ATPase inhibitors on airway cough hypersensitivity induced by allergic airway inflammation in guinea-pigs. Clin Exp Allergy 35(3):262–267PubMedCrossRefGoogle Scholar
  14. 14.
    Lewis CA, Ambrose C, Banner K, Battram C, Butler K, Giddings J, Mok J, Nasra J, Winny C, Poll C (2007) Animal models of cough: literature review and presentation of a novel cigarette smoke-enhanced cough model in the guinea-pig. Pulm Pharmacol Ther 20(4):325–333PubMedCrossRefGoogle Scholar
  15. 15.
    Nasra J, Birrell MA, Poll C, Lewis CA, Belvisi MG (2007) Distinct patterns of response to tussive agents in a guinea-pig model of cough: effect of cigarette smoke exposure. Am J Respir Crit Care Med 41:A667Google Scholar
  16. 16.
    Porter AC, Felder CC (2001) The endocannabinoid nervous system: unique opportunities for therapeutic intervention. Pharmacol Ther 90:45–60PubMedCrossRefGoogle Scholar
  17. 17.
    Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564PubMedCrossRefGoogle Scholar
  18. 18.
    Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterisation of a peripheral receptor for cannabinoids. Nature 365:61–65PubMedCrossRefGoogle Scholar
  19. 19.
    Buckley NE, McCoy KL, Mezey E, Bonner T, Zimmer A, Felder C, Glass M, Zimmer A (2000) Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoiod CB2 receptor. Eur J Parmacol 396:141–149CrossRefGoogle Scholar
  20. 20.
    Griffin G, Fernando SR, Ross RA, McKay NG, Ashford MLJ, Shire D, Huffman JW, Yu S, Lainton JAH, Pertwee RG (1997) Evidence for the presence of CB2 like cannabinoid receptors on peripheral nerve terminals. Eur J Pharmacol 339:53–61PubMedCrossRefGoogle Scholar
  21. 21.
    Galiegue S, Mary S, Marchland J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61PubMedCrossRefGoogle Scholar
  22. 22.
    Richardson JD, Aanonsen L, Hargreaves KM (1998) Antihyperalgesic effects of spinal cannabinoids. Eur J Pharmacol 345:145–153PubMedCrossRefGoogle Scholar
  23. 23.
    Clayton N, Marshall FH, Bountra C, O’Shaughnessy (2002) CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain 96:253–260Google Scholar
  24. 24.
    Malan TP, Ibrahim MM, Vanderah TW, Makriyannis A, Porreca F (2002) Inhibition of pain responses by activation of CB2 cannabinoid receptors. Chem Physics Lipids 121:191–200CrossRefGoogle Scholar
  25. 25.
    Patel HJ, Birrell MA, Crispino N, Hele DJ, Venkatesan P, Barnes PJ, Yacoub MH, Belvisi MG (2003) Inhibition of guinea pig and human sensory nerve activity and the cough reflex in guinea pigs by cannabinoid (CB2) receptor activation. Br J Pharmacol 140:261–268PubMedCrossRefGoogle Scholar
  26. 26.
    Calignano A, Katona I, Desarnaud F, Giuffrida A, La Rana G, Mackie K, Freund TF, Piomelli D (2000) Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature 408:96–101PubMedCrossRefGoogle Scholar
  27. 27.
    Morita K, Kamei J (2003) Antitussive activity of WIN 55212-2, a cannabinoid receptor agonist. Eur J Pharmacol 427:269–272CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Respiratory Pharmacology GroupNational Heart & Lung Institute, NHLI, Faculty of Medicine, Imperial College LondonLondonUK

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