Background: Although neurogenic inflammation via the activation of C fibers in the airway must have an important role in the pathogenesis of asthma, their regulatory mechanism remains uncertain. Objective: The pharmacological profiles of endogenous cannabinoid receptor agonists on the activation of C fibers in airway tissues were investigated and the mechanisms how cannabinoids regulate airway inflammatory reactions were clarified. Methods: The effects of endogenous cannabinoid receptor agonists on electrical field stimulation-induced bronchial smooth muscle contraction, capsaicin-induced bronchoconstriction and capsaicin-induced substance P release in guinea pig airway tissues were investigated. The influences of cannabinoid receptor antagonists and K+ channel blockers to the effects of cannabinoid receptor agonists on these respiratory reactions were examined. Results: Both endogenous cannabinoid receptor agonists, anandamide and palmitoylethanolamide, inhibited electrical field stimulation-induced guinea pig bronchial smooth muscle contraction, but not neurokinin A-induced contraction. A cannabinoid CB2 antagonist, SR 144528, reduced the inhibitory effect of endogenous agonists, but not a cannabinoid CB1 antagonist, SR 141716A. Inhibitory effects of agonists were also reduced by the pretreatment of large conductance Ca2+-activated K+ channel (maxi-K+ channel) blockers, iberiotoxin and charybdotoxin, but not by other K+ channel blockers, dendrotoxin or glibenclamide. Anandamide and palmitoylethanolamide blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea pig airway tissues. Additionally, intravenous injection of palmitoylethanolamide dose-dependently inhibited capsaicin-induced guinea pig bronchoconstriction, but not neurokinin A-induced reaction. However, anandamide did not reduce capsaicin-induced guinea pig bronchoconstriction. Conclusions: These findings suggest that endogenous cannabinoid receptor agonists inhibit the activation of C fibers via cannabinoid CB2 receptors and maxi-K+ channels in guinea pig airways.

1.
Barnes PJ: Neuroeffector mechanisms: the interface between inflammation and neuronal responses. J Allergy Clin Immunol 1996;98:S73–S83.
2.
Joos GF, Pauwels RA: Tachykinin receptor antagonists: potential in airways diseases. Curr Opin Pharmacol 2001;1:235–241.
3.
Murai M, Morimoto H, Maeda Y, Fujii T: Effects of the tripeptide substance P antagonist, FR 113680, on airway constriction and airway edema induced by neurokinins in guinea-pigs. Eur J Pharmacol 1992a;217:23–27.
4.
Murai M, Morimoto H, Maeda Y, Kiyotoh S, Nishikawa M, Fujii T: Effects of FK 224, a novel compound NK1 and NK2 receptor antagonist, on airway constriction and airway edema induced by neurokinins and sensory nerve stimulation in guinea-pigs. J Pharmacol Exp Ther 1992b;262:403–408.
5.
Morimoto H, Yamashita M, Matsuda A, Miyake H, Fujii T: Effects of FR 113680 and FK 224, novel tachykinin antagonists, on cigarette smoke-induced rat tracheal plasma extravasation. Eur J Pharmacol 1992;224:1–5.
6.
Yoshihara S, Chan B, Yamawaki I, Pierangelo G, Ricciardolo FLM, Massion PP, Nadel JA: Plasma extravasation in the rat trachea induced by cold air is mediated by tachykinin release from sensory nerves. Am J Respir Crit Care Med 1995;151:1011–1017.
7.
Ono M, Abe T, Watanabe M, Yamada Y, Yoshihara S: Nedocromil sodium inhibits hypertonic saline-induced plasma extravasation in guinea-pig airways. Biomed Res 1999;20:233–238.
8.
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D: The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997;389:816–824.
9.
Morimoto H, Matsuda A, Ohori M, Fujii T: Effects of ω-conotoxin GVIA on the activation of capsaicin-sensitive afferent sensory nerves in guinea pig airway tissues. Jpn J Pharmacol 1996;71:161–166.
10.
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG: International union of pharmacology. 27. Classification of cannabinoid receptors. Pharmacol Rev 2002;54:161–202.
11.
Munro S, Thomas KL, Abu-Shaar M: Molecular characterization of peripheral receptor for cannabinoids. Nature 1993;365:61–65.
12.
Glass M, Dragunow M, Faull RL: Cannabinoid receptors in the human brain: A detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 1997;77:299–318.
13.
Griffin G, Fernando SR, Ross RA, Mckay NG, Ashford ML, Shire D, Huffman JW, Yu S, Lainton JA, Pertwee RG: Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. Eur J Pharmacol 1997;339:53–61.
14.
Howlett AC, Johnson MR, Melvin LS, Mine GM: Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model. Mol Pharmacol 1988;33:297–302.
15.
Mackie KY, Westenbroek LR, Mitchell R: Cannabinoid activate an inwardly rectifying potassium conductance and inhibit Q-type cannabinoid receptor. J Neurosci 1995;15:6552–6561.
16.
Caulfield MP, Brown DA: Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. Br J Pharmacol 1992;106:231–232.
17.
Mackie K, Hille B: Cannabinoid inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci USA 1992;89:3825–3829.
18.
Fox AJ, Barnes PJ, Venkatesan P, Belvisi MG: Activation of large conductance potassium channels inhibits the afferent and efferent function of airway sensory nerves in the guinea pig. J Clin Invest 1997;99:513–519.
19.
Ray NJ, Jones AJ, Keen P: Morphine, but not sodium cromoglycate, modulates the release of substance P from capsaicin-sensitive neurones in the rat trachea in vitro. Br J Pharmacol 1991;102:797–800.
20.
Wu P, Penman E, Coy DH, Rees LH: Evidence for direct production of somatostatin-14 from a larger precursor than somatostatin-28 in a phaeochromocytoma. Regul Pept 1983;5:219–233.
21.
Mulkey RM, Zucker RS: Action potentials must admit calcium to evoke transmitter release. Nature 1991;350:153–155.
22.
Saria A, Martling CR, Yan Z, Theodorsson-Norheim E, Gamse R, Lundberg JM: Release of multiple tachykinins from capsaicin-sensitive sensory nerves in the lung by bradykinin, histamine, dimethylphenyl piperazinium, and vagal nerve stimulation. Am Rev Respir Dis 1988;137:1330–1335.
23.
Franco-Cereceda A, Saria A, Lundberg JM: Differential release of calcitonin-gene related peptide and neuropeptide Y from the isolated heart by capsaicin, ischemia, nicotine, bradykinin and ouabain. Acta Physiol Scand 1989;135:173–187.
24.
Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R: Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992;258:1946–1949.
25.
Bayewitch M, Avidor-Reiss T, Levy R, Barg J, Mechoulam R, Vogel Z: The peripheral cannabinoid receptor: adenylatecyclase inhibition and G protein coupling. FEBS Lett1995;375:143–147.
26.
Rinaldi-Carmona M, Calandra B, Shire D, Bouaboula M, Oustric D, Barth F, Casellas P, Ferrara P, Le Fur G: Characterization of two cloned human CB1 cannabinoid receptor isoforms. J Pharmacol Exp Ther 1996;278:871–878.
27.
Griffin G, Atkinson PJ, Showalter VM, Martin BR, Abood ME: Evaluation of cannabinoid receptor agonists and antagonists using the guanosine-5′-O-(3-[35S]thio)-triphosphate binding assay in rat cerebellar membranes. J Pharmacol Exp Ther 1998;285:553–560.
28.
Partwee RG: Pharmacology of cannabinoid receptor ligands. Curr Med Chem 1999;6:635–664.
29.
Felder CC, Briley EM, Axelrod J, Simpson JT, Mackie K, Devane WA: Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction. Proc Natl Acad Sci USA 1993;90:7656–7660.
30.
Vogel Z, Barg J, Levy R, Saya D, Heldman E, Mechoulam R: Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase. J Neurochem 1993;61:352–355.
31.
Facci L, Dal Toso R, Romanello S, Buriani A, Skaper SD, Leon A: Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci USA 1995;92:3376–3380.
32.
Tucker RC, Kagaya M, Page CP, Spina D: The endogenous cannabinoid agonist, anandamide stimulates sensory nerves in guinea-pig airways. Br J Pharmacol 2001;132:1127–1135.
33.
Aloe L, Leon A, Levi-Montalcini R: A proposed autacoid mechanism controlling mastocyte behaviour. Agents Actions 1993;39:C145–C147.
34.
Mazzari S, Canella R, Petrelli L, Marcolongo G, Leon A: N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. Eur J Pharmacol 1996;300:227–236.
35.
Abood ME, Martin BR: Molecular neurobiology of the cannabinoid receptor. Int Rev Neurobiol 1996;39:197–221.
36.
Lambert DM, Di Marzo V: The palmitoylethanolamide and oleamide enigmas: are these two fatty acid amides cannabimimetic? Curr Med Chem 1999;6:757–773.
37.
Calignano A, La Rana G, Piomelli D: Antinociceptive activity of the endogenous fatty acid amide, palmitoylethanolamide. Eur J Pharmacol 2001;419:191–198.
38.
Conti S, Costa B, Colleoni M, Parolaro D, Giagnoni G: Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat. Br J Pharmacol 2002;135:181–187.
39.
Miura M, Inoue H, Ichinose M, Kimura K, Katsumata U, Takishima T: Effect of nonadrenergic noncholinergic inhibitory nerve stimulation on the allergic reaction in cat airways. Am Rev Respir Dis 1990;141:29–32.
40.
Miura M, Ichinose M, Kimura K, Katsumata U, Takahashi T, Inoue H, Takishima T: Dysfunction of nonadrenergic noncholinergic inhibitory system after antigen inhalation in actively sensitized cat airways. Am Rev Respir Dis 1992;145:70–74.
41.
Friedman MM, Kaliner MA: Human mast cells and asthma. Am Rev Respir Dis 1987;135:1157–1164.
42.
Cook SA, Welch SP, Lichtman H, Martin BR: Evaluation of cAMP involvement in cannabinoid-induced antinociception. Life Sci 1995;56:2049–2056.
43.
Holzer P: Local effector function of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience 1988;24:739–768.
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