Cough Sensors. III. Opioid and Cannabinoid Receptors on Vagal Sensory Nerves

  • M. G. Belvisi
  • D. J. Hele
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 187)


Cough is a persistent symptom of many inflammatory airways' diseases. Cough is mediated by receptors sited on sensory nerves and then through vagal afferent pathways, which terminate in the brainstem respiratory centre. Cough is often described as an unmet clinical need. Opioids are the only prescription-based anti-tussives currently available in the UK. They possess limited efficacy and exhibit serious unwanted side effects, such as physical dependence, sedation, respiratory depression and gastrointestinal symptoms. There are three classical opioid receptors: the mu, kappa and delta receptors. Peripheral opioid receptors are sited on sensory nerves innervating the airways. A greater understanding of the role of the peripheral and centrally sited opioid receptors is necessary to allow the development of targeted treatments for cough. Because of the limited efficacy and the side-effect profile of the opioids, potential new treatments are sought to alleviate cough. One class of compounds that is currently under examination is the cannabinoids. Like the opioids, cannabinoids have peripheral and centrally sited receptors and also suffer from the blight of unwanted centrally mediated side effects such as sedation, cognitive dysfunction, tachycardia and psychotropic effects. Two cannabinoid receptors have been identified, the CB1 and CB2 receptors, and their distribution varies throughout the peripheral and central nervous system. Encouragingly, early studies with these compounds suggest that it may be possible to separate their antitussive activity from their centrally mediated side effects, with CB2 agonists showing potential as putative new treatments for cough. In this chapter, we describe the opioid and cannabinoid receptors, their distribution and the effects they mediate. Moreover, we highlight their potential advantages and disadvantages in the treatment of cough.


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  1. Adcock JJ (1991) Peripheral opioid receptors and the cough reflex. Respir Med 85 (Suppl A):43–46PubMedCrossRefGoogle Scholar
  2. Ambalavanar R, Tanaka Y, Damirjian M et al. (1999) Laryngeal afferent stimulation enhances Fos immunoreactivity in periaqueductal grey in the cat. J Comp Neurol 409:411–423PubMedCrossRefGoogle Scholar
  3. Atweh SF, Kuhar MJ (1977) Autoradiographic localization of opiate receptors in rat brain. II. The brain stem. Brain Res 129:1–12PubMedCrossRefGoogle Scholar
  4. Atweh SF, Murrin LC, Kuhar MJ (1978) Presynaptic localization of opiate receptors in the vagal and accessory optic systems: an autoradiographic study. Neurophamacology 17:65–71CrossRefGoogle Scholar
  5. Aylward M, Maddock J, Davies DE et al. (1984) Dextromethorphan and codeine: comparison of plasma kinetics and antitussive effects. Eur J Respir Dis 65:283–291PubMedGoogle Scholar
  6. Baekey DM, Morris K, Gestreau C et al. (2001) Medullary respiratory neurones and control of laryngeal motoneurones during fictive eupnoea and cough in the cat. J Physiol 534:565–581PubMedCrossRefGoogle Scholar
  7. Barnes PJ (2001) Neurogenic inflammation in the airways. Respir Physiol 125:145–154PubMedCrossRefGoogle Scholar
  8. Belvisi MG (2002) Overview of the innervation of the lung. Curr Opin Pharmacol 2:211–215 Belvisi MG, Bolser D (2002) Summary: animal models for cough. Pulm Pharmacol Ther 15(3):249–250PubMedCrossRefGoogle Scholar
  9. Belvisi MG, Bolser D (2002) Summary: animal models for cough. Pulm Pharmacol Ther 15(3):249–250PubMedCrossRefGoogle Scholar
  10. Belvisi MG, Geppetti P (2004) Cough 7: current and future drugs for the treatment of chronic cough. Thorax 59(5):438PubMedCrossRefGoogle Scholar
  11. Belvisi MG, Chung KF, Jackson DM et al. (1988) Opioid modulation of non-cholinergic neural bronchoconstriction in guinea-pig in vivo. Br J Pharmacol 95(2):413–418PubMedGoogle Scholar
  12. Bhargava HN, Villar VM, Cortijo J et al. (1997) Binding of [3H][D-Ala2, MePhe4, Gly-ol5] enkephalin, [3H][D-Pen2, D-Pen5]enkephalin, and [3H]U-69,593 to airway and pulmonary tissues of normal and sensitized rats. Peptides 18:1603–1608PubMedCrossRefGoogle Scholar
  13. Bolser DC, McLeod RL, Tulshian DB, Hey JA (2001) Antitussive action of nociceptin in the cat. Eur J Pharmacol 430:107–111PubMedCrossRefGoogle Scholar
  14. Braga PC, Fossati A, Vimercati MG, Caputo R, Guffanti EE (1994) Dextrorphan and dextromethor-phan: comparative antitussive effects on guinea pigs. Drugs Exp Clin Res 20:199–203PubMedGoogle Scholar
  15. Buckley NE, McCoy KL, Mezey E et al. (2000) Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB2 receptor. Eur J Pharmacol 396:141–149PubMedCrossRefGoogle Scholar
  16. Cabot PJ, Crammond T, Smith MT (1996) Quantitative autoradiography of peripheral opioid binding sites in rat lung. Eur J Pharmacol 310:47–53PubMedCrossRefGoogle Scholar
  17. Cabot PJ, Dodd PR, Crammond T et al. (1994) Characterization of non-conventional opioid binding sites in rat and human lung. Eur J Pharmacol 268(2):247–255PubMedCrossRefGoogle Scholar
  18. Cabral GA, Staab A (2005) Effects on the immune system. In: Pertwee RG (ed) Cannabinoids. Handbook of experimental pharmacology, vol. 168. Springer, Berlin, pp 385–423Google Scholar
  19. Caligano A, Katano I, Desarnaud F et al. (2000) Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature 408(6808):96–101CrossRefGoogle Scholar
  20. Callaway JK, King RG, Boura AL (1991) Evidence for peripheral mechanisms mediating the an-titussive actions of opioids in the guinea pig. Gen Pharmacol 22(6):1103–1108PubMedGoogle Scholar
  21. Canning BJ (2007) Encoding of the cough reflex. Pulm Pharmacol Ther 20:396–401PubMedCrossRefGoogle Scholar
  22. Canning BJ, Nori N, Mazzone SB (2006) Vagal afferent nerves regulating the cough reflex. Respir Physiol Neurobiol 152(3):223–242PubMedCrossRefGoogle Scholar
  23. Carr MJ, Lee LY (2006) Plasticity of peripheral mechanisms of cough. Respir Physiol Neurobiol 152(3):298–311PubMedCrossRefGoogle Scholar
  24. Chung KF (2005) Drugs to suppress cough. Expert Opin Investig Drugs 14(1):19–27PubMedCrossRefGoogle Scholar
  25. Chung KF (2007a) Review series: chronic cough: future directions in chronic cough: mechanisms and antitussives. Chron Respir Dis 4(3):159–165CrossRefGoogle Scholar
  26. Chung KF (2007b) Effective antitussives for the cough patient an unmet need. Pulm Pharmacol Ther 20(4):438–445CrossRefGoogle Scholar
  27. Clayton N, Marshall FH, Bountra C et al. (2002) CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain 96:253–260PubMedCrossRefGoogle Scholar
  28. Corboz MR, Fernandez X, Egan RW, Hey JA (2001) Inhibitory activity of nociceptin/orphanin FQ on capsaicin-induced bronchoconstriction in the guinea-pig. Life Sci 69:1203–1211PubMedCrossRefGoogle Scholar
  29. Dashwood MR, Muddle JR, Spyer KM (1988) Opiate receptor subtypes in the nucleus tractus solitarii of the cat: the effect of vagal section. Eur J Pharmacol 155(1–2):85–92PubMedCrossRefGoogle Scholar
  30. Eccles R (2002) The powerful placebo in cough studies? Pulm Pharmacol Ther 15(3):303–308PubMedCrossRefGoogle Scholar
  31. Elmes SJ, Winyard LA, Medhurst SJ et al. (2005) Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat. Pain 118:327–335PubMedCrossRefGoogle Scholar
  32. Fischer A, Forssmann WG, Undem BJ. (1998). Nociceptin-induced inhibition of tachykinergic neurotransmission in guinea pig bronchus. J Pharmacol Exp Ther 285:902–907PubMedGoogle Scholar
  33. Fox B, Bull TB, Guz A (1980) Innervation of alveolar walls in the human lung: an electron microscopic study. J Anat 131:683–692PubMedGoogle Scholar
  34. Freestone C, Eccles R (1997) Assessment of the antitussive efficacy of codeine in cough associated with common cold. J Pharm Pharmacol 49:1045–1049PubMedGoogle Scholar
  35. Frossard N, Barnes PJ (1987) Mu-opioid receptors modulate non-cholinergic constrictor nerves in guinea-pig airways. Eur J Pharmacol 141(3):519–522PubMedCrossRefGoogle Scholar
  36. Galiegue S, Mary S, Marchland J et al. (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61PubMedCrossRefGoogle Scholar
  37. Gestreau C, Bianchi AL, Grelot L (1997) Differential brainstem Fos-like immunoreactivity after laryngeal-induced coughing and its reduction by codeine. J Neurosci 17:9340–9352PubMedGoogle Scholar
  38. Griffin G, Fernando SR, Ross RA et al. (1997) Evidence for the presence of CB2 like cannabinoid receptors on peripheral nerve terminals. Eur J Pharmacol 339:53–61PubMedCrossRefGoogle Scholar
  39. Gundlach A L, Largent BL, Snyder SH (1986) Phencyclidine (PCP) receptors: autoradiographic localization in brain with the selective ligand, [3H]TCP. Brain Res 386:266–279PubMedCrossRefGoogle Scholar
  40. Hanus L, Breuer A, Tchilibon S et al. (1999) HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci USA 96:14228–14333PubMedCrossRefGoogle Scholar
  41. Harris J, Drew LJ, Chapman V (2000) Spinal anandamide inhibits nociceptive transmission via cannabinoid receptor activation in vivo. Neuroreport 11:2817–2819PubMedCrossRefGoogle Scholar
  42. Higenbottam T (2002) Chronic cough and the cough reflex in common lung diseases. Pulm Pharmacol Ther 15(3):241–247PubMedCrossRefGoogle Scholar
  43. Howlett AC (2002) The cannabinoid receptors. Prostaglandins Other Lipid Mediat 68–69:619–631PubMedCrossRefGoogle Scholar
  44. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202PubMedCrossRefGoogle Scholar
  45. Hughes J, Smith TW, Kosterlitz et al. (1975) Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 258:577–580PubMedCrossRefGoogle Scholar
  46. Jiang Q, Takemori AE, Sultana M et al. (1991) Differential antagonism of opioid delta antinoci-ception by [D-Ala2,Leu5,Cys6]enkephalin and naltrindole 5/-isothiocyanate: evidence for delta receptor subtypes. J Pharmacol Exp Ther 257(3):1069–1075PubMedGoogle Scholar
  47. Kamei J (2002) Delta-opioid receptor antagonists as a new concept for central acting antitussive drugs. Pulm Pharmacol Ther 15(3):235–240PubMedCrossRefGoogle Scholar
  48. Kamei J, Tanihara H, Kasuya Y (1990) Antitussive effects of two specific kappa-opioid agonists, U-50,488H and U-62,066E, in rats. Eur J Pharmacol 187:281–286PubMedCrossRefGoogle Scholar
  49. Kamei J, Iwamoto Y, Misawa M, Kasuya Y (1993) Effects of rimcazole, a specific antagonist of sigma sites, on the antitussive effects of non-narcotic antitussive drugs. Eur J Pharmacol 242:209–211PubMedCrossRefGoogle Scholar
  50. Karlsson JA, Lanner AS, Persson CG (1990) Airway opioid receptors mediate inhibition of cough and reflex bronchoconstriction in guinea pigs. J Pharmacol Exp Ther 252:863–868PubMedGoogle Scholar
  51. Kastelik JA, Aziz I, Ojoo JC et al. (2005) Investigation and management of chronic cough using a probability-based algorithm. Eur Respir J 25(2):235–243PubMedCrossRefGoogle Scholar
  52. Kotzer CJ, Haw DW, Dondio G et al. (2000) The antitussive activity of delta-opioid stimulation in guinea pigs. J Pharmacol Exp Ther 292(2):803–809PubMedGoogle Scholar
  53. Lee MG, Undem BJ, Brown C, Carr MJ. (2006) Effect of nociceptin in acid-evoked cough and airway sensory nerve activation in guinea pigs. Am J Respir Crit Care Med 173(3):271–275PubMedCrossRefGoogle Scholar
  54. Lord JA, Waterfield AA, Hughes J et al. (1977) Endogenous opioid peptides: multiple agonists and receptors. Nature 267:495–499PubMedCrossRefGoogle Scholar
  55. Malan TP, Ibrahim MM, Vanderah TW et al. (2002) Inhibition of pain responses by activation of CB2 cannabinoid receptors. Chem Phys Lipids 121:191–200PubMedCrossRefGoogle Scholar
  56. Martin WR, Eades CG, Thompson JA et al. (1976) The effects of morphine- and nalorphine-like drugs in nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197:517–532PubMedGoogle Scholar
  57. Matsuda LA, Lolait SJ, Brownstein MJ et al. (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564PubMedCrossRefGoogle Scholar
  58. McLeod RL, Parra LE, Mutter JC, Erickson CH, Carey GJ, Tulshian DB, Fawzi AB, Smith-Torhan A, Egan RW, Cuss FM et al. (2001) Nociceptin inhibits cough in the guinea-pig by activation of ORL1 receptors. Br J Pharmacol 132:1175–1178PubMedCrossRefGoogle Scholar
  59. Merick B, Reid L (1971) Nerves in rat intra-acinar alveoli: an electron microscope study. Respir Physiol 11:367–377CrossRefGoogle Scholar
  60. Morice AH, Menon MS, Mulrennan SA et al. (2007) Opiate therapy in chronic cough. Am J Respir Crit Care Med 175(4):312–315 Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterisation of a peripheral receptor for cannabinoids. Nature 365:61–65PubMedCrossRefGoogle Scholar
  61. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterisation of a peripheral receptor for cannabinoids. Nature 365:61–65PubMedCrossRefGoogle Scholar
  62. Ohi Y, Yamazaki H, Takeda R et al. (2005) Functional and morphological organization of the nucleus tractus solitarius in the fictive cough reflex of guinea pigs. Neurosci Res 53(2): 201–209PubMedCrossRefGoogle Scholar
  63. Patel HJ, Birrell MA, Crispino N et al. (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
  64. Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74(2):129–180PubMedCrossRefGoogle Scholar
  65. Pertwee RG (2005) Pharmacological actions of cannabinoids. In: Pertwee RG (ed). Cannabinoids. Handbook of experimental pharmacology, vol. 168. Springer, Berlin, pp 1–51Google Scholar
  66. Pertwee RG (2007) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: D9-tetrahydrocannabinol, cannabidiol and D9-tetrahydrocannabivarin. Br J Pharmacol (Sep 10 Epub ahead of print)Google Scholar
  67. Pleuvry BJ (2005) Opioid mechanisms and opioid drugs. Anaesth Intensive Care Med 6(1):30–34CrossRefGoogle Scholar
  68. Porter AC, Felder CC (2001) The endocannabinoid nervous system: unique opportunities for therapeutic intervention. Pharmacol Ther 90:45–60PubMedCrossRefGoogle Scholar
  69. Richardson JD, Aanonsen L, Hargreaves KM (1998a) Antihyperalgesic effects of spinal cannabi-noids. Eur J Pharmacol 345:145–153CrossRefGoogle Scholar
  70. Richardson JD, Kilo S, Hargreaves KM (1998b) Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75:111–119CrossRefGoogle Scholar
  71. Schroeder K, Fahey T (2002) Systematic review of randomised controlled trials of over the counter cough medicines for acute cough in adults. Br Med J 324:1–6CrossRefGoogle Scholar
  72. Sessle BJ, Ball GJ, Lucier GE (1981) Suppressive influences from periaqueductal gray and nucleus raphe magnus on respiration and related reflex activities and on solitary tract neurons, and effect of naloxone. Brain Res 216(1):145–161PubMedCrossRefGoogle Scholar
  73. Sevelius H, Colmore JP (1966) Objective assessment of antitussive agents in patients with chronic cough. J New Drugs 6:216–223PubMedGoogle Scholar
  74. Sevelius H, McCoy JF, Colmore JP (1971) Dose response to codeine in patients with chronic cough. Clin Pharmacol Ther 12:449–455PubMedGoogle Scholar
  75. Shoblock JR (2007) The pharmacology of Ro 64–6198, a systemically active, nonpeptide NOP receptor (opiate receptor-like 1, ORL-1) agonist with diverse preclinical therapeutic activity. CNS Drug Rev (Spring) 13(1):107–136CrossRefGoogle Scholar
  76. Smith J, Owen E, Earis J et al. (2006) Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease. J Allergy Clin Immunol 117:831–835PubMedCrossRefGoogle Scholar
  77. Takahama K, Shirasaki T (2007) Central and peripheral mechanisms of narcotic antitussives: codeine-sensitive and -resistant coughs. Cough 3:1–8CrossRefGoogle Scholar
  78. Undem BJ, Kollarik M (2005) The role of vagal afferent nerves in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2(4):355–360PubMedCrossRefGoogle Scholar
  79. Walter L, Stella N (2004) Cannabinoids and neuroinflammation. Br J Pharmacol 141:775–785PubMedCrossRefGoogle Scholar
  80. Widdicombe JG, Chung KF (2007) Cough. Pulm Pharmacol Ther 20(4):305–306PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • M. G. Belvisi
    • 1
  • D. J. Hele
    • 1
  1. 1.Respiratory Pharmacology, Airway Diseases, National Heart & Lung InstituteImperial College, Guy Scadding BuildingLondonUK

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