Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis.
Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis.
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DOI：
10.1016/j.jaci.2017.02.001
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Basbaum AI
中科院分区：
文献类型：
--
作者：
Cevikbas F;Braz JM;Wang X;Solorzano C;Sulk M;Buhl T;Steinhoff M;Basbaum AI
尽管最近对急性和慢性瘙痒的病理生理学有了深入的了解，但慢性瘙痒仍然是一种经常难以治愈的疾病。慢性瘙痒的主要原因是脊髓GABA能抑制控制功能障碍。为了检验选择性GABA激动剂以及细胞移植衍生的GABA对急性瘙痒具有抗炎作用的假设，以及在通过过度表达TH 2细胞相关细胞因子IL-31（IL-31 Tg小鼠）产生的特应性皮炎转基因小鼠模型中的假设。我们在注射各种致敏剂（组胺、氯喹或内皮素-1）前15-20分钟给野生型和IL-31 Tg小鼠注射GABA-A（蝇蕈醇）或GABA-B（巴氯芬）受体激动剂的组合，并记录给药前后的自发抓挠。我们还测试了在IL-31 Tg小鼠中GABA能中间神经元的前体的椎管内移植的抗炎症特性。系统性蝇蕈醇或巴氯芬对组胺依赖性和非依赖性促炎剂均具有抗炎作用，但单独使用任一配体的治疗窗口非常小。与此相反，巴氯芬和蝇蕈醇的联合阈下剂量产生了显着的协同抗炎作用，没有镇静作用。最后，移植介导的GABA能信号传导的长期增强不仅减少了IL-31 Tg小鼠的自发性抓挠，而且显著地解决了相关的皮肤病变。虽然显然需要更多的研究，但应考虑使用现有批准的GABA激动剂治疗慢性瘙痒，特别是特应性皮炎。
Despite recent insights into the pathophysiology of acute and chronic itch, chronic itch remains an often intractable condition. Among major contributors to chronic itch is dysfunction of spinal cord GABAergic inhibitory controls. To test the hypothesis that selective GABA agonists as well as cell transplant-derived GABA are antipruritic against acute itch and in a transgenic mouse model of atopic dermatitis produced by overexpression of the TH2 cell-associated cytokine, IL-31 (IL-31Tg mice). We injected wild-type and IL-31Tg mice with combinations of GABA-A (muscimol) or GABA-B (baclofen) receptor agonists 15–20 min prior to injection of various pruritogens (histamine, chloroquine or endothelin-1) and recorded spontaneous scratching before and after drug administration. We also tested the antipruritic properties of intraspinal transplantation of precursors of GABAergic interneurons in the IL-31Tg mice. Systemic muscimol or baclofen are antipruritic against both histamine-dependent and independent pruritogens, but the therapeutic window using either ligand alone was very small. In contrast, combined subthreshold doses of baclofen and muscimol produced a significant synergistic antipruritic effect, with no sedation. Finally, transplant-mediated long term enhancement of GABAergic signaling not only reduced spontaneous scratching in the IL-31Tg mice but also dramatically resolved the associated skin lesions. Although additional research is clearly needed, existing approved GABA agonists should be considered in the management of chronic itch, notably atopic dermatitis.
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DOI：
10.1007/978-3-662-44605-8_18
发表时间：
2015-01-01
期刊：
PHARMACOLOGY OF ITCH
影响因子：
--
作者：
Leslie, Tabi Anika;Greaves, Malcolm W.;Yosipovitch, Gil
通讯作者：
Yosipovitch, Gil
影响因子：
3.3
作者：
Akiyama T;Carstens E
通讯作者：
Carstens E
影响因子：
16.2
作者：
Kardon AP;Polgár E;Hachisuka J;Snyder LM;Cameron D;Savage S;Cai X;Karnup S;Fan CR;Hemenway GM;Bernard CS;Schwartz ES;Nagase H;Schwarzer C;Watanabe M;Furuta T;Kaneko T;Koerber HR;Todd AJ;Ross SE
通讯作者：
Ross SE
影响因子：
25
作者：
Han, Liang;Ma, Chao;Liu, Qin;Weng, Hao-Jui;Cui, Yiyuan;Tang, Zongxiang;Kim, Yushin;Nie, Hong;Qu, Lintao;Patel, Kush N.;Li, Zhe;McNeil, Benjamin;He, Shaoqiu;Guan, Yun;Xiao, Bo;LaMotte, Robert H.;Dong, Xinzhong
通讯作者：
Dong, Xinzhong
影响因子：
15.9
作者：
Braz, Joao M.;Juarez-Salinas, Dina;Basbaum, Allan I.
通讯作者：
Basbaum, Allan I.