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: 7384811
• 负责人: John H Winston
• 金额: $ 22.65万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7384811
• 关键词: Abdominal Pain; Acetic Acid; 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; 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; Standards of Weights and Measures; Stimulus; Symptoms; Syndrome; TRPV1 gene; Testing; Visceral; Week; Western Blotting; Work; base; human MAPK14 protein; human study; 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.

描述（由申请人提供）：肠易激综合症 (IBS) 影响着高达 15% 的美国人口，对生活质量、工作效率和巨大的医疗保健费用产生重大负面影响。 IBS 的定义是间歇性腹痛、排便习惯改变以及没有可观察到的生物学异常。尽管尚未确定致病机制，但人类研究表明 IBS 与慢性内脏超敏状态有关。 IBS 患者内脏过敏的产生和维持机制尚不清楚。我们开发了一种大鼠模型，该模型通过向新生大鼠的结肠传递有害刺激而引发，从而导致持久的内脏敏化。成年后（8-12周），这些大鼠表现出对结直肠扩张的敏感性增加、外在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增加。这些变化是在没有炎症或其他解剖异常的组织学证据的情况下发生的，表明外周致敏的伤害性信号传导特征发生了重新编程。该提案将评估 TRPV1 和 p38 以及 ERK MAPK 对该模型中外周敏化发展的贡献。 TRPV1 是在大多数伤害性感觉传入上表达的阳离子通道，可被酸和各种有害和炎症刺激激活。我们的初步结果表明，在新生儿给予乙酸之前TRPV1的拮抗作用减弱了对结直肠扩张的持续敏感性的发展。我们还表明，新生儿乙酸治疗可激活含有结肠传入细胞体的 DRG 中的 p38 和 ERK MAP 激酶。我们假设乙酸在新生儿感觉神经元中激活 TRPV1，通过激活 ERK 1/2 和 p38 MAPK 通路，产生结肠 DRG 神经元的兴奋性增加和基因表达变化。该假设将通过内脏敏感性行为测定、对分离的结肠 DRG 神经元的膜片钳研究、定量 RT-PCR 的基因表达分析、蛋白质印迹和免疫荧光研究进行测试。我们的长期目标是确定导致 IBS 敏化状态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标。