Abstract
The itch–scratch cycle aggravates chronic inflammatory skin diseases. We have previously reported that mice begin to scratch themselves within several minutes after skin-scratching stimulation. This is associated with an increase in release of substance P (SP) from sensory nerve fibers in the skin, and the self-scratching behavior is suppressed by neurokinin-1 receptor (NK-1R) antagonist. Thus, SP may play a pivotal role in self-scratching behavior. The purpose of this study was to investigate the effect of second-generation histamine H1-receptor antagonists on self-scratching behavior in mice. After oral administration of epinastine hydrochloride (epinastine) (total dose 50 ± 5 mg/kg for 7 days) or the vehicle only to ICR mice for 7 days, skin-scratching stimulation was administered to the dorsal skin for 10 min. Self-scratching behavior was recorded by video camera for 10 min. Twenty-four hours later, skin tissue was harvested and stained with toluidine blue. Immunohistochemical staining for SP was performed, and SP and nerve growth factor (NGF) concentrations were measured by enzyme-linked immunosorbent assay. Self-scratching behavior, mast cell degranulation, and NGF concentration decreased, and the length of SP-positive nerve fibers and SP concentrations increased significantly in the epinastine-treated group, when compared with the vehicle control group. We conclude that epinastine inhibits mast cell degranulation by attenuating SP release from sensory nerve fibers, which results in inhibition of self-scratching behavior. These results suggest that second-generation histamine H1-receptor antagonists might efficaciously control itch–scratch cycle-related skin diseases.
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References
Adamus WS, Oldigs-Kerber J, Lohmann HF (1987) Antihistamine activity and central effects of WAL 801 CL in man. Eur J Clin Pharmacol 33:381–385
Andoh T, Nagasawa T, Satoh M, Kuraishi Y (1998) Substance P induction of itch-associated response mediated by cutaneous NK1 tachykinin receptors in mice. J Pharmacol Exp Ther 286:1140–1145
Andoh T, Katsube N, Maruyama M, Kuraishi Y (2001) Involvement of leukotriene B(4) in substance P-induced itch-associated response in mice. J Invest Dermatol 117:1621–1626
Andoh T, Kuraishi Y (2003) Nitric oxide enhances substance P-induced itch-associated responses in mice. Br J Pharmacol 138:202–208
Bilsborough J, Leung DY, Maurer M, Howell M, Boguniewicz M, Yao L, Storey H, LeCiel C, Harder B, Gross JA (2006) IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis. J Allergy Clin Immunol 117:418–425
Braun A, Appel E, Baruch R, Herz U, Botchkarev V, Paus R, Brodie C, Renz H (1998) Role of nerve growth factor in a mouse model of allergic airway inflammation and asthma. Eur J Immunol 28:3240–3251
Bull H, Leslie T, Chopra S, Dowd P (1998) Expression of nerve growth factor receptors in cutaneous inflammation. Br J Dermatol 139:776–783
Dmitrieva N, Shelton D, Rice AS, McMahon SB (1997) The role of nerve growth faction in a model of visceral inflammation. Neuroscience 78:449–459
Fukuishi N, Kan T, Hirose K, Akagi R, Akagi M (1995) Inhibitory effect of epinastine on superoxide generation by rat neutrophils. Jpn J Pharmacol 68:449–452
Gibbs BF, Wierecky J, Welker P, Henz BM, Wolff HH, Grabbe J (2001) Human skin mast cells rapidly release preformed and newly generate TNF-alpha and IL-8 following stimulation with anti-IgE and other secretagogues. Exp Dermatol 10:312–320
Grimstad O, Sawanobori Y, Vestergaard C, Bilsborough J, Olsen UB, Grønhøj-Larsen C, Matsushima K (2009) Anti-interleukin-31-antibodies ameliorate scratching behaviour in NC/Nga mice: a model of atopic dermatitis. Exp Dermatol 18:35–43
Hägermark O, Hökfelt T, Pernow B (1978) Flare and itch induced by substance P in human skin. J Invest Dermatol 71:233–235
Hanifin JM, Cooper KD, Ho VC, Kang S, Krafchik BR, Margolis DJ, Schachner LA, Sidbury R, Whitmore SE, Sieck CK, Van Voorhees AS (2004) Guidelines of care for atopic dermatitis, developed in accordance with the American Academy of Dermatology (AAD)/American Academy of Dermatology Association “Administrative Regulations for Evidence-Based Clinical Practice Guidelines”. J Am Acad Dermatol 50:391–404
Katayama M, Aoki E, Suzuki H, Kawana S (2007) Foot shock stress prolongs the telogen stage of the spontaneous hair cycle in a non-depilated mouse model. Exp Dermatol 16:553–560
Klein PA, Clark RA (1999) An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis. Arch Dermatol 135:1522–1525
Kojima M, Aihara M, Yamada M, Matsukura S, Hirasawa T, Ikezawa Z (2004) Effects of neuropeptides in the development of the atopic dermatitis mouse model. Allergol Int 53:169–178
Kohyama T, Takizawa H, Akiyama N, Sato M, Kawasaki S, Ito K (1997) A novel antiallergic drug epinastine inhibits IL-8 release from human eosinophils. Biochem Biophys Res Commun 230:125–128
Levi-Montalcini R, Dal Toso R, della Valle F, Skaper SD, Leon A (1996) Update of NGF saga. J. Neurol Sci 130:119–127
Lindsay RM, Lockett C, Sternberg J, Winter J (1989) Neuropeptide expression in cultures of adult sensory neurons: modulation of substance P and calcitonin gene-related peptide levels by nerve growth factor. Neuroscience 33:53–65
Matsuda H, Kannan Y, Ushio H, Kiso Y, Kanemoto T, Suzuki H, Kitamura Y (1991) Nerve growth factor induces development of connective tissue-type mast cells in vitro from murine bone marrow cells. J Exp Med 174:7–14
Mendell LM, Albers KM, Davis BM (1999) Neurotrophins, nociceptors, and pain. Microsc Res Technol 45:252–261
Sofroniew MV, Howe CL, Mobley WC (2001) Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 24:1217–1281
Okada T, Hirayama Y, Kishi S, Miyayasu K, Hiroi J, Fujii T (1999) Functional neurokinin NK-1 receptor expression in rat peritoneal mast cells. Inflamm Res 48:274–279
Pernow B (1985) Role of tachykinins in neurogenic inflammation. J Immunol 135:812s–815s
Pincelli C (2000) Nerve growth factor and keratinocytes: a role in psoriasis. Eur J Dermatol 10:85–90
Scholzen T, Armstrong CA, Bunnett NW, Luger TA, Olerud JE, Ansel JC (1998) Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems. Exp Dermatol 7:81–96
Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto H, Kemeny L, Alenius H, Dieu-Nosjean MC, Meller S, Rieker J, Steinhoff M, Hoffmann TK, Ruzicka T, Zlotnik A, Homey B (2006) IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol 117:411–417
Takaoka A, Arai I, Sugimoto M, Yamaguchi A, Tanaka M, Nakaike S (2005) Expression of IL-31 gene transcripts in NC/Nga mice with atopic dermatitis. Eur J Pharmacol 516:180–181
Tamura T, Amano T, Ohmori K, Manabe H (2005) The effects of olopatadine hydrochloride on the number of scratching induced by repeated application of oxazolone in mice. Eur J Pharmacol 524:149–154
Tanizaki H, Kambe N, Nakamura Y, Tanaka A, Matsuda H, Miyachi Y (2008) Oral administration of bepotastine besilate suppressed scratching behavior of atopic dermatitis model NC/Nga mice. Int Arch Allergy Immunol 145:277–282
Toyoda M, Nakamura M, Nakada K, Iida M, Nakamura M, Otani M, Etoh T, Nakagawa H, Morohashi M (2005) Effect of epinastine hydrochloride, a second-generation histamine H1-receptor antagonist, on sensory neurons in vitro. Allergol Int 54:565–572
Toyoda M, Nakamura M, Nakagawa H (2007) Distribution to the skin of epinastine hydrochloride in atopic dermatitis patients. Eur J Dermatol 17:33–36
Tron VA, Coughlin MD, Jang DE, Stanisz J, Sauder DN (1990) Expression and modulation of nerve growth factor in murine keratinocytes (PAM 212). J Clin Invest 85:1085–1089
Wahlgren CF (1999) Itch and atopic dermatitis: an overview. J Dermatol 26:770–779
Weiner-Menzel L, Schulz B, Vakilzadeh F, Czarnetzki BM (1981) Electron microscopical evidence for direct contact between nerve fivers and mast cells. Acta Derma Venerol 61:465–469
Yamaoka J, Di ZH, Sun W, Kawana S (2007) Erratum to “changes in cutaneous sensory nerve fibers induced by skin-scratching in mice”. J Dermatol Sci 47:172–182
Yamaoka J, Kawana S (2007) Rapid changes in substance P signaling and neutral endopeptidase induced by skin-scratching stimulation in mice. J Dermatol Sci 48:123–132
Yamaoka J, Kawana S (2007) A transient unresponsive state of self-scratching behaviour is induced in mice by skin-scratching stimulation. Exp Dermatol 16:737–745
Young M, Oger J, Blanchard MH, Asdourian H, Amos H, Arnason BG (1974) Secretion of a nerve growth factor by primary chick fibroblast cultures. Science 187:361–362
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The authors thank Ms. Fumino Oda and Yuko Yamada for their excellent technical assistance.
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Yilinuer, H., Yamaoka, J. & Kawana, S. Effect of epinastine hydrochloride on murine self-scratching behavior after skin-scratching stimulation. Arch Dermatol Res 302, 19–26 (2010). https://doi.org/10.1007/s00403-009-1006-y
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DOI: https://doi.org/10.1007/s00403-009-1006-y