雌激素易化组胺诱发小鼠瘙痒的外周受体机制研究
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摘要
目的:探究雌激素在小鼠痒觉敏感性性别差异中的作用及外周机制。方法:采用正常雄性、雌性以及去卵巢雌性C57BL/6J鼠作为实验对象,分别检测其皮内注射致痒剂所诱发的搔抓行为,并通过腹腔注射不同的雌激素受体拮抗剂探究其外周受体机制。结果:雌鼠对组胺的痒觉敏感性明显高于雄鼠,氯喹引起的搔抓行为无性别差异;雄鼠注射外源性雌激素后,对组胺的痒觉敏感性明显增强;雌鼠去卵巢后,对组胺的痒觉敏感性则显著降低,外源性补充雌激素可以恢复其正常的痒觉敏感性;腹腔注射非选择性雌激素受体拮抗剂可以降低雌鼠的组胺痒觉敏感性;腹腔注射雌激素受体-α(ER-α)拮抗剂MPP可以降低雌鼠对组胺的敏感性,而雌激素受体-β(ER-β)拮抗剂PHTPP和G蛋白偶联雌激素受体(GPR30)拮抗剂G15则无明显影响。结论:雌激素在外周可以易化组胺引起的瘙痒,是引起小鼠痒觉敏感性性别差异的主要原因,并且其在外周的促痒作用是通过ER-α介导的。
Objective: To explore the role of estrogen in the gender difference of itch sensitivity in mice and its peripheral mechanism. Methods: Normal male mice,female mice and ovariectomized female mice were used as experimental subjects to detect the scratching behavior induced by intradermal injection of itch-inducing agents,and to explore the peripheral receptor mechanisms by intraperitoneal injecting different estrogen receptor antagonists. Results: The itch sensitivity of female mice to histamine was significantly higher than that of male mice,but there was no gender difference in scratching behavior induced by chloroquine; After exogenous injection of estrogen,the itch sensitivity of male mice to histamine increased significantly; After ovariectomy,the itch sensitivity of female mice to histamine was significantly reduced,and exogenous estrogen supplementation could restore to their normal itch sensitivity; Intraperitoneal injection of non-selective estrogen receptor antagonists could reduce itch sensitivity in female mice; And intraperitoneal injection of estrogen receptor-α(ER-α) antagonist MPP could reduce the itch sensitivity of female mice to histamine,while estrogen receptor-β(ER-β) antagonist PHTPP and G protein-conjugated estrogen receptor(GPR30) antagonists G15 had no significant effect. Conclusion: Estrogen can facilitate histamine-induced itch in the periphery,which is the main cause of gender differences in the itch sensitivity of mice,and its peripheral facilitation on itch is mediated by ER-α.
Objective: To explore the role of estrogen in the gender difference of itch sensitivity in mice and its peripheral mechanism. Methods: Normal male mice,female mice and ovariectomized female mice were used as experimental subjects to detect the scratching behavior induced by intradermal injection of itch-inducing agents,and to explore the peripheral receptor mechanisms by intraperitoneal injecting different estrogen receptor antagonists. Results: The itch sensitivity of female mice to histamine was significantly higher than that of male mice,but there was no gender difference in scratching behavior induced by chloroquine; After exogenous injection of estrogen,the itch sensitivity of male mice to histamine increased significantly; After ovariectomy,the itch sensitivity of female mice to histamine was significantly reduced,and exogenous estrogen supplementation could restore to their normal itch sensitivity; Intraperitoneal injection of non-selective estrogen receptor antagonists could reduce itch sensitivity in female mice; And intraperitoneal injection of estrogen receptor-α(ER-α) antagonist MPP could reduce the itch sensitivity of female mice to histamine,while estrogen receptor-β(ER-β) antagonist PHTPP and G protein-conjugated estrogen receptor(GPR30) antagonists G15 had no significant effect. Conclusion: Estrogen can facilitate histamine-induced itch in the periphery,which is the main cause of gender differences in the itch sensitivity of mice,and its peripheral facilitation on itch is mediated by ER-α.
引文
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[2]Ikoma A,Steinhoff M,Stander S,et al.The neurobiology of itch[J].Nat Rev Neurosci,2006,7(7):535-547.DOI:10.1038/nrn1950.
[3]Mochizuki H,Kakigi R.Central mechanisms of itch[J].Clin Neurophysiol,2015,126(9):1650-1660.DOI:10.1016/j.clinph.2014.11.019.
[4]Almey A,Milner TA,Brake WG.Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females[J].Horm Behav,2015,74:125-138.DOI:10.1016/j.yhbeh.2015.06.010.
[5]Baeza I,De Castro NM,Gimenez-Llort L,et al.Ovariectomy,a model of menopause in rodents,causes a premature aging of the nervous and immune systems[J].J Neuroimmunol,2010,219(1-2):90-99.DOI:10.1016/j.jneuroim.2009.12.008.
[6]Bottai G,Mancina R,Muratori M,et al.17beta-estradiol protects human skin fibroblasts and keratinocytes against oxidative damage[J].J Eur Acad Dermatol Venereol,2013,27(10):1236-1243.DOI:10.1111/j.1468-3083.2012.04697.x.
[7]Velnar T,Bailey T,Smrkolj V.The wound healing process:an overview of the cellular and molecular mechanisms[J].J Int Med Res,2009,37(5):1528-1542.DOI:10.1177/147323000903700531.
[8]陈琼.160例慢性自发性荨麻疹临床特点分析[J].中外医疗,2013,32(36):40-41.DOI:10.16662/j.cnki.1674-0742.2013.36.113.
[9]Dale HH.On some physiological actions of ergot[J].J Physiol,1906,34(3):163-206.
[10]Stander S,Stumpf A,Osada N,et al.Gender differences in chronic pruritus:women present different morbidity,more scratch lesions and higher burden[J].Br J Dermatol,2013,168(6):1273-1280.DOI:10.1111/bjd.12267.
[11]Umeuchi H,Kawashima Y,Aoki CA,et al.Spontaneous scratching behavior in MRL/lpr mice,a possible model for pruritus in autoimmune diseases,and antipruritic activity of a novel kappa-opioid receptor agonist nalfurafine hydrochloride[J].Eur J Pharmacol,2005,518(2-3):133-139.DOI:10.1016/j.ejphar.2005.06.019.
[12]Green AD,Young KK,Lehto SG,et al.Influence of genotype,dose and sex on pruritogen-induced scratching behavior in the mouse[J].Pain,2006,124(1-2):50-58.DOI:10.1016/j.pain.2006.03.023.
[13]Je H.Guyton and Hall textbook of medical physiology[M].City:aunders/Elsevier,2011.
[14]Labrie F.All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause[J].JSteroid Biochem Mol Biol,2015,145:133-138.DOI:10.1016/j.jsbmb.2014.06.001.
[15]Raine-Fenning NJ,Brincat MP,Muscat-Baron Y.Skin aging and menopause:implications for treatment[J].Am J Clin Dermatol,2003,4(6):371-378.DOI:10.2165/00128071-200304060-00001.
[16]Thornton MJ.Estrogens and aging skin[J].Dermatoendocrinol,2013,5(2):264-270.DOI:10.4161/derm.23872.
[17]Craft RM.Modulation of pain by estrogens[J].Pain,2007,132Suppl 1:S3-12.DOI:10.1016/j.pain.2007.09.028.
[18]Cooke PS,Nanjappa MK,Ko C,et al.Estrogens in Male Physiology[J].Physiol Rev,2017,97(3):995-1043.DOI:10.1152/physrev.00018.2016.
[19]Yamaura K,Tomono A,Suwa E,et al.Sex-related differences in SLIGRL-induced pruritus in mice[J].Life Sci,2014,94(1):54-57.DOI:10.1016/j.lfs.2013.10.036.
[20]Kuiper GG,Carlsson B,Grandien K,et al.Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta[J].Endocrinology,1997,138(3):863-870.DOI:10.1210/endo.138.3.4979.
[21]Harris HA,Katzenellenbogen JA,Katzenellenbogen BS.Characterization of the biological roles of the estrogen receptors,ERalpha and ERbeta,in estrogen target tissues in vivo through the use of an ERalpha-selective ligand[J].Endocrinology,2002,143(11):4172-4177.DOI:10.1210/en.2002-220403.