Bidirectional control of airway responsiveness by endogenous cannabinoids

Article metrics

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 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).

  2. 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).

  3. 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).

  4. 4

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

  5. 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).

  6. 6

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

  7. 7

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

  8. 8

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

  9. 9

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

  10. 10

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

  11. 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).

  12. 12

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

  13. 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).

  14. 14

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

  15. 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).

  16. 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).

  17. 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).

  18. 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).

  19. 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).

  20. 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).

  21. 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).

  22. 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).

  23. 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).

  24. 24

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

  25. 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).

  26. 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).

  27. 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).

  28. 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).

  29. 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).

  30. 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).

Download references

Acknowledgements

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.).

Author information

Correspondence to D. Piomelli.

Rights and permissions

Reprints and Permissions

About this article

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.