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Spinal Mechanisms of itch Transmission

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Neuroscience Bulletin 2018年第1期34卷 156-164页

作者： Devin M.Barry Admire Munanairi Zhou-Feng Chen Center for the Study of itch Washington University School of Medicine Department of Anesthesiology Washington University School of Medicine Department of Psychiatry Washington University School of Medicine Developmental Biology Washington University School of Medicine

Peripheral itch stimuli are transmitted by sensory neurons to the spinal cord dorsal horn, which then transmits the information to the brain. The molecular and cellular mechanisms within the dorsal horn for itch transmission have only been investigated and identified during the past ten years. This review covers the progress that has been made in identifying the peptide families in sensory neurons and the receptor families in dorsal horn neurons as putative itch transmitters, with a focus on gastrin-releasing peptide （GRP）--GRP receptor signaling. Also discussed are the signaling mechanisms, including opioids, by which various types of itch are transmitted and modulated, as well as the many conflicting results arising from recent studies.

关键词： itch Neuropeptides Spinal cord DRG GPCR signaling

Population coding of somatic sensations

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Neuroscience Bulletin 2012年第2期28卷 91-99页

作者： Qiufu Ma Dana-Farber Cancer Institute and Department of Neurobiology Harvard Medical School Boston Massachusetts 02115USA

The somatic sensory system in^udes a variety of sensory modalities, such as touch, pain, itch, and temperature sensitivity. The coding of these modalities appears to be best explained by the population-coding theory, which is com- posed of the following features. First, an individual somatic sensory afferent is connected with a specific neural circuit or network （for simplicity, a sensory-labeled line）, whose isolated activation is sufficient to generate one specific sensation under normal conditions. Second, labeled lines are interconnected through local excitatory and inhibitory interneurons. As a result, activation of one labeled line could modulate, or provide gate control of, another labeled line. Third, most sensory fibers are polymodal, such that a given stimulus placed onto the skin often activates two or multiple sensory-labeled lines; crosstalk among them is needed to generate one dominant sensation. Fourth and under pathological conditions, a disruption of the antagonistic interaction among labeled lines could open normally masked neuronal pathways, and allow a given sensory stimulus to evoke a new sensation, such as pain evoked by innocuous mechanical or thermal stimuli and itch evoked by painful stimuli. As a result of this, some sensory fibers operate along distinct labeled lines under normal versus pathological conditions. Thus, a better understanding of the neural network underlying labeled line crosstalk may provide new strategies to treat chronic pain and itch.

关键词： developmental neurobiology dorsal root ganglion pain pathways itch spinal dorsal horn

Expression of Notch pathway components (Numb, itch, and Siah-1) in colorectal tumors: A clinicopathological study

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World Journal of Gastroenterology 2020年第26期26卷 3814-3833页

作者： Sinem Cil Gonulcu Betul Unal Ibrahim Cumhur Bassorgun Mualla Ozcan Hasan Senol Coskun Gulsum Ozlem Elpek Department of Pathology Akdeniz UniversitySchool of MedicineAntalya 07070Turkey Department of Oncology Akdeniz UniversitySchool of MedicineAntalya 07070Turkey

BACKGROUND The role of the Notch pathway in carcinogenesis and tumor progression has been demonstrated in many organs,including the colon.Accordingly,studies aimed at developing therapies targeting this pathway in various cancers require the identification of several factors that may play a role in regulating Notch-1 expression.Although Numb,itch,and seven in absentia homolog-1(Siah-1)have been shown to contribute to the regulation of Notch signaling,their role in colorectal carcinogenesis and tumor progression has not been fully elucidated to date.AIM To evaluate Numb,itch,and Siah-1 expression in colorectal tumors to clarify their relationship with Notch-1 expression and their role in carcinogenesis and tumor behavior.METHODS Expression of Notch-1,Numb,itch,and Siah-1 was investigated in 50 colorectal carcinomas,30 adenomas,and 20 healthy colonic tissues by immunohistochemistry and quantitative real-time polymerase chain reaction(PCR)analyses.RESULTS In contrast to Notch-1,which is expressed at higher levels in tumor tissues and adenomas,expression of Numb,itch,and Siah-1 was stronger and more frequent in normal mucosa(Pitch,and Siah-1 was absent or reduced in tumors with these clinicopathological parameters(Pitch,and Siah-1 correlated with improved survival(Pitch,and Siah-1 expression is associated with carcinogenesis.Our data also suggest that these three proteins might be involved in the Notch-1 pathway during colorectal carcinoma(CRC)progression and might play

关键词： Colorectal adenomas Colorectal cancer Notch-1 Numb itch Siah-1

Aberrant Th2 inflammation drives dysfunction of alveolar macrophages and susceptibility to bacterial pneumonia

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Cellular & Molecular Immunology 2018年第5期15卷 480-492页

作者： Emily K Moser Natania S Field Paula M Oliver Cell Pathology Division Children’s Hospital of PhiladelphiaPhiladelphiaPA 19104USA Cell and Molecular Biology Program Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104USA Department of Pathology and Laboratory Medicine University of PennsylvaniaPhiladelphiaPA 19104USA

The ubiquitin ligase,itch,is required to prevent autoinflammatory disease in mice and humans.itch-deficient mice develop lethal pulmonary inflammation characterized by the production of Th2 cytokines(for example,interleukin-4(IL-4));however,the contribution of itch to immune defense against respiratory pathogens has not been determined.We found that itch-deficient mice were highly susceptible to intranasal infection with the respiratory pathogen Klebsiella pneumoniae.Infected itch-deficient mice exhibited increased immune cell infiltration,cytokine levels and bacterial burden in the respiratory tract compared with control mice.However,numbers of resident alveolar macrophages were reduced in the lungs from itch-deficient mice both before and after infection.High levels of Th2 cytokines in the respiratory tract correlated with deceased alveolar macrophages,and genetic ablation of IL-4 restored alveolar macrophages and host defense to K.pneumoniae in itch-deficient mice,suggesting that loss of alveolar macrophages occurred as a consequence of Th2 inflammation.Adoptive transfer of itch−/−CD4+T cells into Rag−/−mice was sufficient to drive reduction in numbers of itch-replete alveolar macrophages.Finally,we found that Stat6 signaling downstream of the IL-4 receptor directly reduced fitness of alveolar macrophages when these cells were exposed to the itch−/−inflamed respiratory tract.These data suggest that Th2 inflammation directly impairs alveolar macrophage fitness in itch−/−mice,and elucidate a previously unappreciated link between Th2 cells,alveolar macrophages and susceptibility to bacterial infection.

关键词： alveolar macrophage bacterial pneumonia itch Th2 cell

Descending Modulation of Spinal itch Transmission by Primary Somatosensory Cortex

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Neuroscience Bulletin 2021年第9期37卷 1345-1350页

作者： Zi-Han Wu Han-Yu Shao Yuan-Yuan Fu Xiao-Bo Wu De-Li Cao Sheng-Xiang Yan Wei-Lin Sha Yong-Jing Gao Zhi-Jun Zhang Department of Human Anatomy School of MedicineNantong UniversityNantong 226001China Institute of Pain Medicine Institute of Nautical MedicineNantong UniversityNantong 226019China Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226001China

Dear Editor,itch(pruritus)is an unpleasant somatic sensation that is accompanied by the desire to scratch.While itch provides a warning signal that protects us from potential threats in normal conditions,severe or chronic itch associated with dermatosis or systemic diseases is often difficult to alleviate and causes severe skin and tissue damage.

关键词： sensation itch Spinal

Specific Patterns of Spinal Metabolite Ratio Underlying a-Me-5-HTevoked Pruritus Compared with Compound 48/80 Based on Proton Nuclear Magnetic Resonance Spectroscopy

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Current Medical Science 2020年第4期40卷 761-766页

作者： Ying-le CHEN Zhi-gang HE Qian WANG Hong-bing XIANG Li FAN Jun XIONG Department of Anesthesiology the First Affiliated Quanzhou Hospital of Fujian Medical UniversityQuanzhou 362000China Emergency Medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Anesthesiology and Pain Medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Hepatobiliary Surgery Center Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China

Summary:Mechanisms of pruritus are implicated in the dysregulation of the metabolites in the spinal cord.We investigated pruritus behavioral testing in three groups of young adult male C57B1/6 mice,including one group treated with normal saline,while the other groups intradermally injected with a-Me-5-HT(histamine-independent pruritogen),compound 48/80(histaminedependent pruritogen)at the nape skin of the neck,respectively.Proton nuclear magnetic resonance spectroscopy(MRS)was used to compare spinal metabolites from the vertebral cervical among three groups,and to study the association of spinal metabolite ratio and pruritus intensity.The MRS-measured N-acetylaspartate-to-myoinositol ratio(NAA/Ins)was significantly correlated with the number of scratches between normal saline group and 48/80 group or a-Me-5-HT group(both P<0.0001),indicating that NAA/Ins may be a robust surrogate marker of histamine-independent/dependent pruritogen.There was significant difference in Glu/Ins between normal saline group and 48/80 group(P=0.017),indicating that Glu/Ins may be a surrogate marker of histamine-dependent pruritogen,while GABA/Ins was highly significantly different between normal saline group and a-Me-5-HT group(P=0.008),suggesting that GABA/Ins may be a surrogate marker of histamineindependent pruritogen.MRS may reflect the extent of pruritus intensity elicited by a-Me-5-HT and compound 48/80 with sensitivity similar to the number of scratches,and above potential markers need to be further validated in pre-clinical and clinical treatment trials.

关键词： itch pruritus intensity spinal cord metabolomics proton nuclear magnetic resonance

Intradermal administration of formalin to the cheek induces itch as well as pain behaviors in rats

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上海交通大学学报（医学版） 2018年第10期38卷 1167-1173页

作者：钱佳红 GAO Po 戎伟芳 Department of Anatomy and Physiology Shanghai Jiao Tong University College of Basic Medical SciencesShanghai 200025China

Objective · Formalin is a classic and most widely used algogenic substance, but its itchy effect is not clear. The present study aims to explore the hypothesis that formalin may induce itch as well as pain. Methods · Flinching, as well as licking and forelimb wiping of the site of injection were counted as pain responses, whereas biting and hind paw scratching of the cheek were counted as itchy responses. To discriminate formalin-induced sensations in rats, the irritant(saline as control) was injected, and then pain and itchy responses were recorded.Results · Intraplantar injection of formalin elicited biphasic behavior responses characterized as flinching, as well as biting or licking of the hind paw without significant gender differences. Following intradermal administration of formalin to the cheek, rats exhibited episodic forelimb wiping of the cheek, representative of pain. No gender difference was noticed for this type of behavior. In addition, episodes of hind paw scratches of the cheek, representative of pruritoceptive responses, also occurred. Interestingly, hind paw scratches appeared to be more pronounced in male than in female rats. Conclusion · Intradermal administration of formalin elicits pruritoceptive as well as nociceptive responses in rats.

关键词： formalin cheek model itch pain

E3泛素连接酶itch在单侧输尿管结扎诱导的肾纤维化中的作用及机制

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E3泛素连接酶Itch在单侧输尿管结扎诱导的肾纤维化中的作用及机制

作者：张伟河北医科大学

学位级别：硕士

目的:肾纤维化是各种慢性肾脏病(chronic kidney disease,CKD)进展过程的重要途径,其中肾小管上皮细胞的上皮-间质转分化(epithelial-mesenchymal transition,EMT)和细胞外基质沉积,胶原增多有着极其重要的作用,此过程的确切机制至今仍... 详细信息

目的:肾纤维化是各种慢性肾脏病(chronic kidney disease,CKD)进展过程的重要途径,其中肾小管上皮细胞的上皮-间质转分化(epithelial-mesenchymal transition,EMT)和细胞外基质沉积,胶原增多有着极其重要的作用,此过程的确切机制至今仍未彻底阐明。蛋白质泛素化是一种关键的翻译后修饰过程,是泛素蛋白酶体系统(UPS)降解泛素相关蛋白质所必需的。目前公认的的泛素蛋白酶体系统包括激活酶(E1)、结合酶(E2)还有连接酶(E3)。首先,泛素激活的过程是由E1执行的;然后E2将泛素分子转给E3;最后,E3就会催化泛素分子及其靶蛋白分子之间的共价结合。目前发现的连接酶E3按照一定的结构划分为三个家族:RING(zinc-binding RING finger adaptor)家族,HECT(homologous with the carboxyl end of E6AP)家族和U-box(amodified cyclic motif)家族。E3酶有以下几种主要功能:1)识别特定底物2)转移泛素分子3)HECT家族的E3参与构成多泛素链所需的残基4)RING家族的E3可以将泛素分子从E2转至目标蛋白。itch其作为E3泛素连接酶HECT家族中的重要的一分子,经过大量的研究与探索,发现了它参与了哺乳动物的生长发育过程,以及多种疾病的发生发展过程,并且是以免疫性疾病、炎症性疾病和肿瘤的发展中的作用及机制研究的最多,但itch对于在肾间质纤维化的确切作用尚未阐述明了。本研究拟采用单侧输尿管梗阻模型小鼠和和TGF-β刺激条件下的人肾小管上皮细胞(human renal tubular cell lines,HK-2),观察itch的表达情况及其对Wnt通路和纤维化的影响,并在此基础上,应用itch敲除小鼠,在HK-2细胞中过表达itch基因,探究E3泛素连接酶itch对肾小管上皮细胞转分化和纤维化的影响。方法:1.探究itch在UUO小鼠肾组织中的表达和对TGF-β诱导的HK-2转分化中的作用6-8周龄的C57BL/6背景的itch小鼠和itch小鼠分为假手术组(Sham)、UUO 3天组、UUO 7天组、UUO 14天组,itch敲除对照组(itch),itch敲除并UUO 14天组(UUO+itch),每组各5只。UUO模型切开游离输尿管并结扎,假手术组不结扎。造模成功后留取肾脏,RT-PCR检测itch的m RNA的表达,HE、MASSON染色观察各组小鼠肾脏的病变情况,Western blot和免疫组织化学(Immunohistochemistry,IHC)检测E-cadherin、α-SMA、Collagen I和Fibronectin的蛋白表达情况。2.探究itch在UUO小鼠肾脏Wnt通路的影响Western blot和免疫组织化学(Immunohistochemistry,IHC)检测假手术组(Sham)、UUO 14天组,itch敲除对照组(itch),itch敲除并UUO 14天组(UUO+itch)的β-catenin和DVL2的蛋白表达情况。3.观察itch在TGF-β刺激条件下的HK-2细胞的表达用不同浓度的TGF-β刺激HK-2细胞48 h,分别为0、2.5、5、10、20 ng/ml,Western blot筛选出itch变化程度最明显的浓度,再以此浓度刺激HK-2细胞持续不同的时间,分别为0、24、48、72 h,用RT-PCR和Western blot观察检测itch的表达情况。从中选出的itch变化最明显的时间点与TGF-β浓度进行后续实验。4.探究过表达itch对TGF-β刺激下的HK-2细胞转分化的影响我们将HK-2细胞随机分为了正常组(N)、TGF-β组(TGF-β)、TGF-β刺激加空载pcmv-MCS-3Flag质粒转染组(TGF-β+C)、TGF-β刺激加itch过表达pcmv-MCS-3Flag-itch质粒转染组(TGF-β+OE),终止培养后,Western blot和细胞免疫荧光(Immunofluorescent,IF)检测itch、E-cadherin、α-SMA和Fibronectin的蛋白表达,RT-PCR检测E-cadherin、α-SMA和Fibronectin的m RNA表达。5.探究Wnt通路抑制剂IWR-1对TGF-β刺激条件下HK-2转分化的影响我们将HK-2细胞随机分为了正常组(N)、TGF-β组(TGF-β)、TGF-β和IWR-1共同刺激组(TGF-β+IWR-1),终止培养后,Western blot和细胞免疫荧光检测E-cadherin、α-SMA和Fibronectin的蛋白表达。6.探究itch对TGF-β刺激下HK-2细胞Wnt/β-catenin通路的影响我们将HK-2细胞随机分为了正常组(N)、T

关键词： itch Wnt EMT 人肾小管上皮细胞 UUO

Enhanced scratching elicited by apruritogen and an algogen in a mouse model of contact hypersensitivity

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中国药理学与毒理学杂志 2015年第S1期29卷 62-63页

作者： KaiFU Lin-taoQU StevenG.SHIMADA HongNIE RobertHLaMOTTE Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research College of Pharmacy Jinan University Guangzhou 510632 China Department of Anesthesiology Yale University School of Medicine New Haven CT 06520 USA

OBJECTIVE To investigate whether normally pruritic and algesic chemicals evoked abnormal itch-or pain-like behaviors in the mouse after the development of contact hypersensitivity(CHS),an animal model of allergic contact dermatitis.METHODS Mice previously sensitized to a hapten(squaric acid dibutylester)applied to the abdomen,exhibited spontaneous itch-like scratching and pain-like wiping directed to the site on the cheek of the CHS elicited by a subsequent challenge with the same hapten.At 24 hafter the second challenge,each mouse was placed in the test container and its pontaneous behavior was recorded for 30 min.Then each mouse received an intradermal injection into the previously challenged cheek of 5μL of a chemical solution(a normal saline vehicle alone or the vehicle containing either histamine(5μg),BAM8-22(1μg)or bradykinin(2.65μg)and returned to the container to have its behavior recorded for another 30 min.RESULTS In comparison with the mean numbers of site-directed behaviors evoked by the injection of normal saline vehicle,bradykinin evoked significantly more wipes but not more bouts of scratching whereas histamine and BAM8-22 each elicited significantly more bouts of scratching but not more wipes.In comparison with acetone treated controls,the CHS mice displayed a significantly greater number of bouts of spontaneous site-directed scratching and wiping to the SADBE challenged skin after the second challenge(scratching:1.2±0.67 vs 16.4±3.40,wiping:1.0±0.75 vs 27.8±5.96,respectively,Pitch-like scratching behavior evoked by a

关键词： contact hypersensitivity itch pain pruritogen algo