We have previously reported that S-777469 [1-([6-ethyl-1-(4-fluorobenzyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carbonyl]amino)-cyclohexanecarboxylic acid], a novel cannabinoid type 2 receptor (CB2) agonist, significantly suppressed compound 48/80-induced scratching behavior in mice in a dose-dependent manner when it was administered orally. Here, we demonstrated that the inhibitory effects of S-777469 on compound 48/80-induced scratching behavior are reversed by pretreatment with SR144528, a CB2-selective antagonist. In addition, we investigated the effects of S-777469 on itch-associated scratching behavior induced by several pruritogenic agents in mice and rats. S-777469 significantly suppressed scratching behavior induced by histamine or substance P in mice or by serotonin in rats. In contrast, the H1-antihistamine fexofenadine clearly inhibited histamine-induced scratching behavior but did not affect scratching behavior induced by substance P or serotonin. Moreover, S-777469 significantly inhibited histamine-induced peripheral nerve firing in mice. In conclusion, these results suggest that S-777469 produces its antipruritic effects by inhibiting itch signal transmission through CB2 agonism.

1.
Rothman S: Physiology of itching. Physiol Rev 1941;21:357-381.
2.
Twycross R, Greaves MW, Handwerker H, Jones EA, Libretto SE, Szepietowski JC, et al: Itch: scratching more than the surface. QJM 2003;96:7-26.
3.
Handwerker HO, Forster C, Kirchhoff C: Discharge patterns of human C-fibers induced by itching and burning stimuli. J Neurophysiol 1991;66:307-315.
4.
Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjörk HE: Specific C-receptors for itch in human skin. J Neurosci 1997;17:8003-8008.
5.
Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjörk HE, Handwerker HO: Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol 2003;89:2441-2448.
6.
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al: International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002;54:161-202.
7.
Herkenham M, Lynn AB, Little MD, Ross Johnson M, Melvin LS, De Costa BR, et al: Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 1990;87:1932-1936.
8.
Pertwee RG: Evidence for the presence of CB1 cannabinoid receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid receptors. Life Sci 1999;65:597-605.
9.
Ahluwalia J, Urban L, Bevan S, Capogna M, Nagy I: Cannabinoid 1 receptors are expressed by nerve growth factor- and glial cell-derived neurotrophic factor-responsive primary sensory neurones. Neuroscience 2002;110:747-753.
10.
Klein TW, Newton CA, Friedman H: Cannabinoids and the immune system. Pain Res Manag 2001;6:95-101.
11.
Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenberg D, Horowitz M, et al: HU-308: a specific agonist for CB2, a peripheral cannabinoid receptor. Proc Natl Acad Sci USA 1999;96:14228-14233.
12.
Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, et al: Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci USA 2003;100:10529-10533.
13.
Manera C, Cascio MG, Benetti V, Allarà M, Tuccinardi T, Martinelli A, et al: New 1,8-naphthyridine and quinoline derivatives as CB2 selective agonists. Bioorg Med Chem Lett 2007;17:6505-6510.
14.
Khanolkar AD, Lu D, Ibrahim M, Duclos RI Jr, Thakur GA, Malan TP Jr, Porreca F, Veerappan V, Tian X, George C, Parrish DA, Papahatjis DP, Makriyannis A: Cannabilactones: a novel class of CB2 selective agonists with peripheral analgesic activity. J Med Chem 2007;50:6493-6500.
15.
Omura H, Kawai M, Shima A, Iwata Y, Ito F, Masuda T, et al: The SAR studies of novel CB2 selective agonists, benzimidazolone derivatives. Bioorg Med Chem Lett 2008;18:3310-3314.
16.
Yao BB, Hsieh G, Daza AV, Fan Y, Grayson GK, Garrison TR, et al: Characterization of a cannabinoid CB2 receptor-selective agonist, A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], using in vitro pharmacological assays, in vivo pain models, and pharmacological magnetic resonance imaging. J Pharmacol Exp Ther 2009;328:141-151.
17.
Dvorak M, Watkinson A, McGlone F, Rukwied R: Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin. Inflamm Res 2003;52:238-245.
18.
Ständer S, Reinhardt HW, Luger TA: Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus. Hautarzt 2006;57:801-807.
19.
Odan M, Ishizuka N, Hiramatsu Y, Inagaki M, Hashizume H, Fujii Y, et al: Discovery of S-777469: an orally available CB2 agonist as an antipruritic agent. Bioorg Med Chem Lett 2012;22:2803-2806.
20.
Nojima H, Carstens E: 5-Hydroxytryptamine (5-HT)2 receptor involvement in acute 5-HT-evoked scratching but not in allergic pruritus induced by dinitrofluorobenzene in rats. J Pharmacol Exp Ther 2003;306:245-252.
21.
Ikoma A, Steinhoff M, Ständer S, Yosipovitch G, Schmelz M: The neurobiology of itch. Nat Rev Neurosci 2006;7:535-547.
22.
Ständer S, Weisshaar E, Luger TA: Neurophysiological and neurochemical basis of modern pruritus treatment. Exp Dermatol 2008;7:161-169.
23.
Liu T, Ji RR: New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms? Pflugers Arch 2013;465:671-685.
24.
Kuraishi Y, Nagasawa T, Hayashi K, Satoh M: Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. Eur J Pharmacol 1995;275:229-233.
25.
Anand U, Otto WR, Sanchez-Herrera D, Facer P, Yiangou Y, Korchev Y, et al: Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons. Pain 2008;138:667-680.
26.
Sagar DR, Kelly S, Millns PJ, O'Shaughnessey CT, Kendall DA, Chapman V: Inhibitory effects of CB1 and CB2 receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats. Eur J Neurosci 2005;22:371-379.
27.
Ständer S, Schmelz M, Metze D, Luger T, Rukwied R: Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J Dermatol Sci 2005;38:177-188.
28.
Nackley AG, Zvonok AM, Makriyannis A, Hohmann AG: Activation of cannabinoid CB2 receptors suppresses C-fiber responses and windup in spinal wide dynamic range neurons in the absence and presence of inflammation. J Neurophysiol 2004;92:3562-3574.
29.
Maekawa T, Nojima H, Kuraishi Y: Itch-associated responses of afferent nerve innervating the murine skin: different effects of histamine and serotonin in ICR and ddY mice. Jpn J Pharmacol 2000;84:462-466.
30.
Andoh T, Katsube N, Maruyama M, Kuraishi Y: Involvement of leukotriene B4 in substance P-induced itch-associated response in mice. J Invest Dermatol 2001;117:1621-1626.
31.
Kajihara Y, Murakami M, Imagawa T, Otsuguro K, Ito S, Ohta T: Histamine potentiates acid-induced responses mediating transient receptor potential V1 in mouse primary sensory neurons. Neuroscience 2010;166:292-304.
32.
Nicholson R, Small J, Dixon AK, Spanswick D, Lee K: Serotonin receptor mRNA expression in rat dorsal root ganglion neurons. Neurosci Lett 2003;337:119-122.
33.
Andoh T, Nagasawa T, Kuraishi Y: Expression of tachykinin NK1 receptor mRNA in dorsal root ganglia of the mouse. Brain Res Mol Brain Res 1996;35:329-332.
34.
Andoh T, Kuraishi Y: Expression of BLT1 leukotriene B4 receptor on the dorsal root ganglion neurons in mice. Brain Res Mol Brain Res 2005;137:263-266.
35.
Beltramo M, Bernardini N, Bertorelli R, Campanella M, Nicolussi E, Fredduzzi S, et al: CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci 2006;23:1530-1538.
36.
Bouaboula M, Dussossoy D, Casellas P: Regulation of peripheral cannabinoid receptor CB2 phosphorylation by the inverse agonist SR 144528. J Biol Chem 1999;274:20397-20405.
37.
Grimsey NL, Goodfellow CE, Dragunow M, Glass M: Cannabinoid receptor 2 undergoes Rab5-mediated internalization and recycles via a Rab11-dependent pathway. Biochim Biophys Acta 2011;1813:1554-1560.
38.
Atwood BK, Wager-Miller J, Haskins C, Straiker A, Mackie K: Functional selectivity in CB2 cannabinoid receptor signaling and regulation: implications for the therapeutic potential of CB2 ligands. Mol Pharmacol 2012;81:250-263.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.