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Bidirectional control of airway responsiveness by endogenous cannabinoids


Smoking marijuana or administration of its main active constituent, Δ9-tetrahydrocannabinol (Δ9-THC), may exert potent dilating effects on human airways1,2,3,4. But the physiological significance of this observation and its potential therapeutic value are obscured by the fact that some asthmatic patients respond to these compounds with a paradoxical bronchospasm3,5. The mechanisms underlying these contrasting responses remain unresolved. Here we show that the endogenous cannabinoid anandamide exerts dual effects on bronchial responsiveness in rodents: it strongly inhibits bronchospasm and cough evoked by the chemical irritant, capsaicin, but causes bronchospasm when the constricting tone exerted by the vagus nerve is removed. Both effects are mediated through peripheral CB1 cannabinoid receptors found on axon terminals of airway nerves. Biochemical analyses indicate that anandamide is synthesized in lung tissue on calcium-ion stimulation, suggesting that locally generated anandamide participates in the intrinsic control of airway responsiveness. In support of this conclusion, the CB1 antagonist SR141716A enhances capsaicin-evoked bronchospasm and cough. Our results may account for the contrasting bronchial actions of cannabis-like drugs in humans, and provide a framework for the development of more selective cannabinoid-based agents for the treatment of respiratory pathologies.

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Figure 1: Anandamide inhibits bronchospasm and coughing in guinea-pigs by activating peripheral CB1 receptors.
Figure 2: Anandamide causes bronchoconstriction in vagotomized, atropine-treated guinea pigs by activating peripheral CB1 receptors.
Figure 3: Localization of CB1 receptors on axon terminals and preterminal segments in rat lungs.
Figure 4: Intrinsic effects of the CB1 antagonist SR141716A on capsaicin-evoked bronchospasm and cough.
Figure 5: Ca2+-dependent biosynthesis of anandamide in rat lung tissue.
Figure 6: Ca2+-dependent biosynthesis of anandamide precursors in rat lung.


  1. Vachon, L., Fitzgerald, M. X., Solliday, N. H., Gould, I. A. & Gaensler, E. A. Single-dose effects of marihuana smoke. Bronchial dynamics and respiratory-center sensitivity in normal subjects. New Engl. J. Med. 288, 985– 989 (1973).

    CAS  Article  Google Scholar 

  2. Tashkin, D. P., Shapiro, B. J., Lee, Y. E. & Harper, C. E. Effects of smoked marijuana in experimentally induced asthma. Am. Rev. Respir. Dis. 112, 377–386 (1975).

    CAS  PubMed  Google Scholar 

  3. Tashkin, D. P. et al. Bronchial effects of aerosolized delta 9-tetrahydrocannabinol in healthy and asthmatic subjects. Am. Rev. Respir. Dis. 115, 57–65 (1977).

    CAS  PubMed  Google Scholar 

  4. Iversen, L. L. The Science of Marijuana (Oxford Univ. Press, Oxford, 2000).

    Google Scholar 

  5. Abboud, R. T. & Sanders, H. D. Effect of oral administration of delta-9-tetrahydrocannabinol on airway mechanics in normal and asthmatic subjects. Chest 70, 480– 485 (1976).

    CAS  Article  Google Scholar 

  6. Devane, W. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946 –1949 (1992).

    ADS  CAS  Article  Google Scholar 

  7. Di Marzo, V. et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686– 691 (1994).

    ADS  CAS  Article  Google Scholar 

  8. Szallasi, A. & Blumberg, P. M. Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol. Rev. 51, 159– 212 (1999).

    CAS  PubMed  Google Scholar 

  9. Barnes, P. J. Modulation of neurotransmission in airways. Physiol. Rev. 72, 699–729 (1992).

    ADS  CAS  Article  Google Scholar 

  10. Rinaldi-Carmona, M. et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 350, 240 –244 (1994).

    CAS  Article  Google Scholar 

  11. Rinaldi-Carmona, M. et al. SR144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther. 284, 644–650 (1998).

    CAS  PubMed  Google Scholar 

  12. Calignano, A., La Rana, G., Giuffrida, A. & Piomelli, D. Control of pain initiation by endogenous cannabinoids. Nature 394, 277–281 (1998).

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  14. Widdicombe, J. G. Afferent receptors in the airways and cough. Respir. Physiol. 114, 5–15 (1998).

    CAS  Article  Google Scholar 

  15. Zygmunt, P. M., Julius, I., Di Marzo, V. & Hogestatt, E. D. Anandamide—the other side of the coin. Trends Pharmacol. Sci. 21, 43–44 (2000).

    CAS  Article  Google Scholar 

  16. Ishac, E. J. et al. Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. Br. J. Pharmacol. 118, 2023–2028 (1996).

    CAS  Article  Google Scholar 

  17. Coutts, A. A., Pertwee, R. G., Fernando, S. R. & Nash, J. E. Inhibition by cannabinoid receptor agonists of acetylcholine release from guinea-pig myenteric plexus. Br. J. Pharmacol. 121, 1557–1566 (1997).

    CAS  Article  Google Scholar 

  18. Richardson, J. D., Kilo, S. & Hargreaves, K. M. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75, 111–119 (1998).

    CAS  Article  Google Scholar 

  19. Katona, I. et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J. Neurosci. 19, 4544–4558 (1999).

    CAS  Article  Google Scholar 

  20. Rice, W., Shannon, J. M., Burton, F. & Fiedeldey, D. Expression of a brain-type cannabinoid receptor (CB1) in alveolar type II cells in the lung: regulation by hydrocortisone. Eur. J. Pharmacol. 327, 227–232 ( 1997).

    CAS  Article  Google Scholar 

  21. Landsman, R. S., Burkey, T. H., Consroe, P., Roeske, W. R. & Yamamura, H. I. SR141716A is an inverse agonist at the human cannabinoid CB1 receptor. Eur. J. Pharmacol. 334, R1–R2 (1997).

    CAS  Article  Google Scholar 

  22. Sugiura, T. et al. Transacylase-mediated and phosphodiesterase-mediated synthesis of N-arachidonoylethanolamine, an endogenous cannabinoid-receptor ligand, in rat brain microsomes. Eur. J. Biochem. 240, 53–62 (1996).

    CAS  Article  Google Scholar 

  23. Cadas, H., di Tomaso, E. & Piomelli, D. Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J. Neurosci. 17, 1226–1242 (1997).

    CAS  Article  Google Scholar 

  24. Van Hoozen, B. E. & Cross, C. E. Marijuana. Respiratory tract effects. Clin. Rev. Allergy Immunol. 15, 243–269 (1997).

    CAS  Article  Google Scholar 

  25. Piomelli, D., Giuffrida, A., Calignano, A. & Rodríguez de Fonseca, F. The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol. Sci. 21, 218– 224 (2000).

    CAS  Article  Google Scholar 

  26. Bolster, D. C., Del Prado, M., O'Reilly, S., Mingo, G. & Hey, J. A. Evan's blue dye blocks capsaicin-induced cough and bronchospasm in the guinea pig. Eur. J. Pharmacol. 276, R1–R3 (1995).

    Article  Google Scholar 

  27. Samhoun, M. N. & Piper, P. J. The combined use of isolated strips of guinea-pig lung parenchyma and ileum as a sensitive and selective bioassay for leukotriene B4. Prostaglandins 27, 711–724 ( 1984).

    CAS  Article  Google Scholar 

  28. Csiffary, A., Gorcs, T. J. & Palkovits, M. Neuropeptide Y innervation of ACTH-immunoreactive neurons in the arcuate nucleus of rats: a correlated light and electron microscopic double immunolabeling study. Brain Res. 506, 215–222 (1990).

    CAS  Article  Google Scholar 

  29. Désarnaud, F., Cadas, H. & Piomelli, D. Anandamide amidohydrolase activity in rat brain microsomes: Identification and partial characterization. J. Biol. Chem. 270, 6030–6035 (1995).

    Article  Google Scholar 

  30. Giuffrida, A., Rodríguez de Fonseca, F. & Piomelli, D. Quantification of bioactive acylethanolamides in rat plasma by electrospray mass spectrometry. Anal. Biochem. 280, 87–93 ( 2000).

    CAS  Article  Google Scholar 

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We thank S. Chen, M. Elefante, G. Fabozzi, G. Goda, E. Oswáld and R. Russo for excellent experimental assistance; T. Dinh, H. Kim and F. Nava for reading the manuscript critically; and B. Vigh for discussion. This research was supported from the National Institute of Drug Abuse (D.P. and K.M.), by the Howard Hughes Medical Institute and OTKA (T.F.), and by MURST (A.C.).

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Calignano, A., Kátona, I., Désarnaud, F. et al. Bidirectional control of airway responsiveness by endogenous cannabinoids . Nature 408, 96–101 (2000).

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