Mechanisms of sensitzation in a rat model of chronic visceral hypersensitivity

慢性内脏超敏反应大鼠模型的致敏机制

• 批准号: 7653643
• 负责人: John H Winston
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653643
• 关键词: Abdominal Pain; Acetic Acids; Acids; Adult; Affect; Afferent Neurons; Attenuated; Behavior; Behavioral; Behavioral Assay; Biological; Biological Assay; Brain-Derived Neurotrophic Factor; Cations; Characteristics; Chemicals; Chronic; Colon; Colorectal; Deformity; Development; Event; Exhibits; Extracellular Signal Regulated Kinases; Gene Expression; Generations; Genes; Genus Cola; Habits; Health Care Costs; Human; Hyperalgesia; Hypersensitivity; Immunofluorescence Immunologic; Inflammation; Inflammatory; Injury; Intestines; Irritable Bowel Syndrome; Knockout Mice; MAPK11 gene; MAPK14 gene; Maintenance; Mechanical Stimulation; Mechanics; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Neonatal; Neurons; Nociception; Nociceptors; Pathway interactions; Patients; Peripheral; Population; Process; Productivity; Quality of life; Rattus; Reverse Transcriptase Polymerase Chain Reaction; Sensory; Signal Transduction; Spinal Ganglia; Stimulus; Symptoms; Syndrome; TRPV1 gene; Testing; Visceral; Western Blotting; Work; base; human MAPK14 protein; inhibitor/antagonist; insight; mitogen-activated protein kinase p38; mustard oil; neuronal cell body; nociceptive response; patch clamp; prevent; receptor

DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) affects up to 15% of the U.S. population, produces significant negative effects on quality of life, work productivity and significant health care costs. IBS is defined by the occurrence of intermittent periods of abdominal pain and altered bowel habits and the absence of observable biological abnormalities. Although no pathogenic mechanisms have been defined, human studies demonstrate that IBS is associated with a state of chronic visceral hypersensitivity. The mechanisms responsible for the generation and maintenance of visceral hypersensitivity in IBS patients are not known. We have developed a rat model initiated by a noxious stimulus delivered to the colon of neonatal rats that result in long-lasting visceral sensitization. As adults (8-12 weeks), these rats display an increased sensitivity to colorectal distention, increased excitability of extrinsic colon-specific sensory neurons, and gene plasticity in the S1 dorsal root ganglia. These changes occur in the absence of histological evidence of inflammation or other anatomical abnormalities and suggest a reprogramming of nociceptive signaling characteristic of peripheral sensitization. This proposal will evaluate the contributions of TRPV1 and p38 and ERK MAPK to the development of peripheral sensitization in this model. TRPV1 is a cation channel expressed on the majority of nociceptive sensory afferents that is activated by acid and various noxious and inflammatory stimuli. Our preliminary results show that antagonism of TRPV1 prior to neonatal administration of acetic acid attenuates the development of the persistent sensitivity to colorectal distention. We also show that neonatal acetic acid treatment activates p38 and ERK MAP kinases in DRG containing the soma of colon afferents. We hypothesize that TRPV1 activation by acetic acid in neonatal sensory neurons produces increased excitability and changes in gene expression in colon DRG neurons via activation of the ERK 1/2 and p38 MAPK pathways. This hypothesis will be tested using a behavioral assay for visceral sensitivity, patch clamp studies on isolated colon DRG neurons, gene expression analysis by quantitative RT-PCR, western blot and immunofluorescence studies. Our long-term objective is to identify key molecular events responsible for the initiation and perpetuation of the sensitized state in IBS and provide targets for new pharmacological approaches for the treatment of this syndrome.

肠易激综合征（IBS）影响高达15%的美国人口，对生活质量，工作效率和显著的医疗保健成本产生显著的负面影响。IBS的定义是间歇性腹痛和排便习惯改变的发生以及没有可观察到的生物学异常。虽然没有确定致病机制，但人体研究表明，IBS与慢性内脏高敏感性状态有关。IBS患者内脏高敏感性的产生和维持机制尚不清楚。我们已经开发了一种大鼠模型，该模型由递送到新生大鼠结肠的有害刺激引发，导致持久的内脏敏化。成年后（8-12周），这些大鼠显示出对结直肠扩张的敏感性增加，外源性结肠特异性感觉神经元的兴奋性增加，以及S1背根神经节的基因可塑性。这些变化发生在没有炎症或其他解剖学异常的组织学证据的情况下，表明外周致敏的伤害性信号特征的重编程。本提案将评估TRPV 1和p38以及ERK MAPK对该模型中外周致敏发展的贡献。TRPV 1是在大多数伤害性感觉传入上表达的阳离子通道，其被酸和各种有害和炎症刺激激活。我们的初步研究结果表明，拮抗TRPV 1之前，新生儿管理的乙酸衰减的发展持续敏感性结直肠扩张。我们还表明，新生儿乙酸处理激活p38和ERK MAP激酶在DRG中含有索马的结肠传入。我们推测，TRPV 1激活乙酸在新生儿感觉神经元产生增加的兴奋性和变化的基因表达在结肠DRG神经元通过激活ERK 1/2和p38 MAPK途径。将使用内脏敏感性的行为测定、对分离的结肠DRG神经元的膜片钳研究、通过定量RT-PCR的基因表达分析、蛋白质印迹和免疫荧光研究来检验该假设。我们的长期目标是确定负责IBS致敏状态的启动和持续的关键分子事件，并为治疗该综合征的新药理学方法提供靶点。