Model of Chronic Itch in Aged Mice: Beneficial Effects of Drugs Affecting Descending Modulatory Systems
DOI:
https://doi.org/10.2340/actadv.v104.39950Keywords:
pruritus in the elderly, mechanical alloknesis, descending inhibitory systemAbstract
Pruritus in the elderly, particularly those cases without skin dryness or other identifiable causes, makes treatment challenging due to the lack of evidence regarding the therapeutic effects of antipruritics. This study proposes an age-related alloknesis mouse model for an evaluation system for such cases, and aimed to investigate the effectiveness and mechanisms of action of several drugs commonly used as antipruritics in Japan, utilizing this model. Mice 69–80 weeks old were used as aged mice, and the level of mechanical alloknesis was counted as the number of scratching behaviours in response to innocuous stimuli. Bepotastine, neurotropin, pregabalin, baricitinib, and abrocitinib were used as antipruritics, and yohimbine and methysergide as inhibitors of the descending inhibitory pathway. The findings suggest that mechanical alloknesis in aged mice is a suitable animal model for assessing pruritus in the elderly without xerosis, and pregabalin, neurotropin, baricitinib, and abrocitinib may be effective antipruritics in the elderly through activating both the noradrenergic and serotonergic descending inhibitory pathways. These findings may be useful for the selection of antipruritics for pruritus in the elderly without skin lesions or dryness.
Downloads
References
Chung BY, Um JY, Kim JC, Kang SY, Park CW, Kim HO. Pathophysiology and treatment of pruritus in elderly. Int J Mol Sci 2020; 22.
https://doi.org/10.3390/ijms22010174 DOI: https://doi.org/10.3390/ijms22010174
Berger TG, Steinhoff M. Pruritus in elderly patients: eruptions of senescence. Semin Cutan Med Surg 2011; 30: 113-117.
https://doi.org/10.1016/j.sder.2011.04.002 DOI: https://doi.org/10.1016/j.sder.2011.04.002
Yalçin B, Tamer E, Toy GG, Oztaş P, Hayran M, Alli N. The prevalence of skin diseases in the elderly: analysis of 4099 geriatric patients. Int J Dermatol 2006; 45: 672-676.
https://doi.org/10.1111/j.1365-4632.2005.02607.x DOI: https://doi.org/10.1111/j.1365-4632.2005.02607.x
Valdes-Rodriguez R, Mollanazar NK, González-Muro J, Nattkemper L, Torres-Alvarez B, López-Esqueda FJ, et al. Itch prevalence and characteristics in a Hispanic geriatric population: a comprehensive study using a standardized itch questionnaire. Acta Derm Venereol 2015; 95: 417-421.
https://doi.org/10.2340/00015555-1968 DOI: https://doi.org/10.2340/00015555-1968
Norman RA. Xerosis and pruritus in the elderly: recognition and management. Dermatol Ther 2003; 16: 254-259.
https://doi.org/10.1046/j.1529-8019.2003.01635.x DOI: https://doi.org/10.1046/j.1529-8019.2003.01635.x
Valdes-Rodriguez R, Stull C, Yosipovitch G. Chronic pruritus in the elderly: pathophysiology, diagnosis and management. Drugs Aging 2015; 32: 201-215.
https://doi.org/10.1007/s40266-015-0246-0 DOI: https://doi.org/10.1007/s40266-015-0246-0
Satoh T, Yokozeki H, Murota H, Tokura Y, Kabashima K, Takamori K, et al. 2020 guidelines for the diagnosis and treatment of cutaneous pruritus. J Dermatol 2021; 48: e399-e413.
https://doi.org/10.1111/1346-8138.16066 DOI: https://doi.org/10.1111/1346-8138.16066
Beauregard S, Gilchrest BA. A survey of skin problems and skin care regimens in the elderly. Arch Dermatol 1987; 123: 1638-1643. DOI: https://doi.org/10.1001/archderm.123.12.1638
https://doi.org/10.1001/archderm.1987.01660360066014 DOI: https://doi.org/10.1001/archderm.1987.01660360066014
Polat M, Yalçin B, Calişkan D, Alli N. Complete dermatological examination in the elderly: an exploratory study from an outpatient clinic in Turkey. Gerontology 2009; 55: 58-63.
https://doi.org/10.1159/000129683 DOI: https://doi.org/10.1159/000129683
White-Chu EF, Reddy M. Dry skin in the elderly: complexities of a common problem. Clin Dermatol 2011; 29: 37-42.
https://doi.org/10.1016/j.clindermatol.2010.07.005 DOI: https://doi.org/10.1016/j.clindermatol.2010.07.005
Feng J, Luo J, Yang P, Du J, Kim BS, Hu H. Piezo2 channel-Merkel cell signaling modulates the conversion of touch to itch. Science 2018; 360: 530-533.
https://doi.org/10.1126/science.aar5703 DOI: https://doi.org/10.1126/science.aar5703
Braz JM, Hamel K, Craik V, Rodriguez-Rosado S, Bhardwaj K, Jewell M, et al. Pain and itch processing in aged mice. J Pain 2023; 10.1016/j.jpain.2023.07.018.
https://doi.org/10.1016/j.jpain.2023.07.018 DOI: https://doi.org/10.1016/j.jpain.2023.07.018
Takahashi N, Tominaga M, Kosaka R, Kamata Y, Umehara Y, Matsuda H, et al. Involvement of µ-opioid receptors and κ-opioid receptors in itch-related scratching behaviour of imiquimod-induced psoriasis-like dermatitis in mice. Acta Derm Venereol 2017; 97: 928-933.
https://doi.org/10.2340/00015555-2704 DOI: https://doi.org/10.2340/00015555-2704
Tsukumo Y, Matsumoto Y, Miura H, Yano H, Manabe H. Gabapentin and pregabalin inhibit the itch-associated response induced by the repeated application of oxazolone in mice. J Pharmacol Sci 2011; 115: 27-35.
https://doi.org/10.1254/jphs.10173FP DOI: https://doi.org/10.1254/jphs.10173FP
Kamo A, Tominaga M, Matsuda H, Kina K, Kamata Y, Umehara Y, et al. Neurotropin suppresses itch-related behavior in NC/Nga mice with atopic dermatitis-like symptoms. J Dermatol Sci 2016; 81: 212-215.
https://doi.org/10.1016/j.jdermsci.2015.11.014 DOI: https://doi.org/10.1016/j.jdermsci.2015.11.014
Hylden JL, Wilcox GL. Intrathecal morphine in mice: a new technique. Eur J Pharmacol 1980; 67: 313-316.
https://doi.org/10.1016/0014-2999(80)90515-4 DOI: https://doi.org/10.1016/0014-2999(80)90515-4
Komiya E, Tominaga M, Hatano R, Kamikubo Y, Toyama S, Sakairi H, et al. Peripheral endomorphins drive mechanical alloknesis under the enzymatic control of CD26/DPPIV. J Allergy Clin Immunol 2022; 149: 1085-1096.
https://doi.org/10.1016/j.jaci.2021.08.003 DOI: https://doi.org/10.1016/j.jaci.2021.08.003
Takeuchi Y, Takasu K, Ono H, Tanabe M. Pregabalin, S-(+)-3-isobutylgaba, activates the descending noradrenergic system to alleviate neuropathic pain in the mouse partial sciatic nerve ligation model. Neuropharmacology 2007; 53: 842-853.
https://doi.org/10.1016/j.neuropharm.2007.08.013 DOI: https://doi.org/10.1016/j.neuropharm.2007.08.013
Kawamura M, Ohara H, Go K, Koga Y, Ienaga K. Neurotropin induces antinociceptive effect by enhancing descending pain inhibitory systems involving 5-HT3 and noradrenergic alpha2 receptors in spinal dorsal horn. Life Sci 1998; 62: 2181-2190.
https://doi.org/10.1016/S0024-3205(98)00195-7 DOI: https://doi.org/10.1016/S0024-3205(98)00195-7
Moniaga CS, Tominaga M, Takamori K. Mechanisms and management of itch in dry skin. Acta Derm Venereol 2020; 100: adv00024.
https://doi.org/10.2340/00015555-3344 DOI: https://doi.org/10.2340/00015555-3344
Zhao N, Gu M, Yang W, Zhang M, Tian Q, Ru L, et al. Increased ZAP70 is involved in dry skin pruritus in aged mice. Biomed Res Int 2016; 2016: 6029538.
https://doi.org/10.1155/2016/6029538 DOI: https://doi.org/10.1155/2016/6029538
Fan JJ, Gao B, Song AQ, Zhu YJ, Zhou J, Li WZ, et al. Spinal cord NLRP1 inflammasome contributes to dry skin induced chronic itch in mice. J Neuroinflammation 2020; 17: 122.
https://doi.org/10.1186/s12974-020-01807-3 DOI: https://doi.org/10.1186/s12974-020-01807-3
Matsuda KM, Sharma D, Schonfeld AR, Kwatra SG. Gabapentin and pregabalin for the treatment of chronic pruritus. J Am Acad Dermatol 2016; 75: 619-625.e616.
https://doi.org/10.1016/j.jaad.2016.02.1237 DOI: https://doi.org/10.1016/j.jaad.2016.02.1237
Hata T, Kita T, Itoh E, Oyama R, Kawabata A. Mechanism of the analgesic effect of neurotropin. Jpn J Pharmacol 1988; 48: 165-173.
https://doi.org/10.1254/jjp.48.165 DOI: https://doi.org/10.1254/jjp.48.165
Yue J, Jiao S, Xiao Y, Ren W, Zhao T, Meng J. Comparison of pregabalin with ondansetron in treatment of uraemic pruritus in dialysis patients: a prospective, randomized, double-blind study. Int Urol Nephrol 2015; 47: 161-167.
https://doi.org/10.1007/s11255-014-0795-x DOI: https://doi.org/10.1007/s11255-014-0795-x
Shimada N, Niwa Y, Hotta K, Igarashi T, Takeuchi M. Pregabalin for postherpetic itch: a case report. JA Clin Rep 2020; 6: 24.
https://doi.org/10.1186/s40981-020-00330-x DOI: https://doi.org/10.1186/s40981-020-00330-x
Kaku H, Fujita Y, Yago H, Naka F, Kawakubo H, Nakano K, et al. Study on pruritus in hemodialysis patients and the antipruritic effect of neurotropin: plasma levels of substance P, somatostatin, IgE, PTH and histamine. Nihon Jinzo Gakkai Shi 1990; 32: 319-326.
Torrelo A, Rewerska B, Galimberti M, Paller A, Yang CY, Prakash A, et al. Efficacy and safety of baricitinib in combination with topical corticosteroids in paediatric patients with moderate-to-severe atopic dermatitis with an inadequate response to topical corticosteroids: results from a phase III, randomized, double-blind, placebo-controlled study (BREEZE-AD PEDS). Br J Dermatol 2023; 189: 23-32.
https://doi.org/10.1093/bjd/ljad096 DOI: https://doi.org/10.1093/bjd/ljad096
Perche PO, Cook MK, Feldman SR. Abrocitinib: a new FDA-approved drug for moderate-to-severe atopic dermatitis. Ann Pharmacother 2023; 57: 86-98.
https://doi.org/10.1177/10600280221096713 DOI: https://doi.org/10.1177/10600280221096713
Huang IH, Chung WH, Wu PC, Chen CB. JAK-STAT signaling pathway in the pathogenesis of atopic dermatitis: an updated review. Front Immunol 2022; 13: 1068260.
https://doi.org/10.3389/fimmu.2022.1068260 DOI: https://doi.org/10.3389/fimmu.2022.1068260
Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, Guo CJ, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell 2017; 171: 217-228.e213.
https://doi.org/10.1016/j.cell.2017.08.006 DOI: https://doi.org/10.1016/j.cell.2017.08.006
Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest 2010; 120: 3779-3787.
https://doi.org/10.1172/JCI43766 DOI: https://doi.org/10.1172/JCI43766
Pertovaara A. Noradrenergic pain modulation. Prog Neurobiol 2006; 80: 53-83.
https://doi.org/10.1016/j.pneurobio.2006.08.001 DOI: https://doi.org/10.1016/j.pneurobio.2006.08.001
Liu QQ, Yao XX, Gao SH, Li R, Li BJ, Yang W, et al. Role of 5-HT receptors in neuropathic pain: potential therapeutic implications. Pharmacol Res 2020; 159: 104949.
https://doi.org/10.1016/j.phrs.2020.104949 DOI: https://doi.org/10.1016/j.phrs.2020.104949
Miyahara Y, Funahashi H, Naono-Nakayama R, Haruta-Tsukamoto A, Nishimori T, Ishida Y. Role of serotonin and noradrenaline in the acute itch processing in mice. Eur J Pharmacol 2019; 850: 118-125.
https://doi.org/10.1016/j.ejphar.2019.02.013 DOI: https://doi.org/10.1016/j.ejphar.2019.02.013
Miyahara Y, Funahashi H, Naono-Nakayama R, Haruta-Tsukamoto A, Muroi C, Kogoh Y, et al. Serotonin and noradrenaline modulate chronic itch processing in mice. Eur J Pharmacol 2020; 883: 173319.
https://doi.org/10.1016/j.ejphar.2020.173319 DOI: https://doi.org/10.1016/j.ejphar.2020.173319
Koga K, Shiraishi Y, Yamagata R, Tozaki-Saitoh H, Shiratori-Hayashi M, Tsuda M. Intrinsic braking role of descending locus coeruleus noradrenergic neurons in acute and chronic itch in mice. Mol Brain 2020; 13: 144.
https://doi.org/10.1186/s13041-020-00688-0 DOI: https://doi.org/10.1186/s13041-020-00688-0
Colpaert FC, Niemegeers CJ, Janssen PA. In vivo evidence of partial agonist activity exerted by purported 5-hydroxytryptamine antagonists. Eur J Pharmacol 1979; 58: 505-509.
https://doi.org/10.1016/0014-2999(79)90326-1 DOI: https://doi.org/10.1016/0014-2999(79)90326-1
Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, et al. Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiedebergs Arch Pharmacol 2004; 370: 114-123.
https://doi.org/10.1007/s00210-004-0951-4 DOI: https://doi.org/10.1007/s00210-004-0951-4
Zhao ZQ, Liu XY, Jeffry J, Karunarathne WK, Li JL, Munanairi A, et al. Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling. Neuron 2014; 84: 821-834.
https://doi.org/10.1016/j.neuron.2014.10.003 DOI: https://doi.org/10.1016/j.neuron.2014.10.003
Additional Files
Published
How to Cite
License
Copyright (c) 2024 Go Kojima, Eriko Komiya, Kotaro Honda, Takahide Kaneko, Yasushi Suga, Mitsutoshi Tominaga, Kenji Takamori
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All digitalized ActaDV contents is available freely online. The Society for Publication of Acta Dermato-Venereologica owns the copyright for all material published until volume 88 (2008) and as from volume 89 (2009) the journal has been published fully Open Access, meaning the authors retain copyright to their work.
Unless otherwise specified, all Open Access articles are published under CC-BY-NC licences, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material for non-commercial purposes, provided proper attribution to the original work.
