Neurochemical mechanisms of visceral pain

内脏痛的神经化学机制

基本信息

批准号：
8541893
负责人：
RICHARD J Traub
金额：
$ 31.03万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8541893
关键词：
Address Agonist Behavioral Binding Biochemical Biological Assay Cell membrane Clinical Colorectal Disease Estradiol Estrogen Receptor 1 Estrogen Receptor 2 Estrogen Receptors Estrogens Estrous Cycle Female Genomics Goals Gonadal Hormones Hormonal Hypersensitivity Inflammation Intestines Irritable Bowel Syndrome Knowledge MAP Kinase Gene MAPK14 gene MAPK8 gene Mediating Membrane Menstrual cycle Modeling N-Methyl-D-Aspartate Receptors Nerve Nervous system structure Neuroglia Neurons Nociception Organ Pain Pathway interactions Patients Pharmacology Phenotype Physiological Physiology Posterior Horn Cells Process Progesterone Progestins Protein Isoforms Rattus Receptor Activation Reporting Role Sensory Process Severities Signal Transduction Spinal Spinal Cord Steroid Receptors Steroids Stimulus Symptoms Syndrome System Testing Therapeutic Intervention Time Viscera Visceral Visceral pain Woman Women&apos s Role chronic pain interdisciplinary approach male medical attention men multidisciplinary neurochemistry new therapeutic target non-genomic novel therapeutic intervention public health relevance receptor receptor binding receptor function research study response sex transcription factor

项目摘要

Pain arising from visceral organs is one of the most common forms of pain in the clinical setting, and one of the most frequent reasons why patients seek medical attention. In general, women are more sensitive to pain than men and functional bowel disorders, such as irritable bowel syndrome (IBS), are 2-3 times more prevalent in women. The severity of IBS symptoms in women fluctuates with the menstrual cycle and visceral sensitivity in rats fluctuates across the estrous cycle, suggesting gonadal hormones modulate nociceptive processing of visceral stimuli. However, the mechanisms underlying hormonal modulation of visceral pain are poorly understood. For example, estrogen has been reported to have pro- and anti-nociceptive effects, confounding a clear understanding of hormonal modulation of visceral pain. Two isoforms of the estrogen receptor, ER¿ and ER¿, mediate both transcriptional modulation and rapid effects of estrogen signaling in the nervous system, sometimes in opposing directions. In this application we will test the hypotheses that these 2 receptors modulate different aspects of visceral nociceptive processing at the level of the spinal cord and the interaction of these signaling systems can have an effect on visceral hypersensitivity associated with IBS. Utilizing a systems level approach we will address the following specific aims. Specific Aim 1 will test the hypotheses that [1] estrogen receptors modulate colorectal sensory processing at the level of the spinal cord and that [2] the two isoforms of the estrogen receptor (ER¿ and ER¿) in the spinal cord differentially modulate the visceromotor response to colorectal distention (CRD). As a sub-Aim to [1], we will address the negative hypothesis that estradiol does not directly modulate the response of colonic afferents to CRD. A multidisciplinary electrophysiological, immunocytochemical and behavioral approach will be used to determine if ER¿ or ER¿ is expressed in colonic afferent DRG neurons and if agonists at these receptors modulate the physiology of colonic primary afferents. Specific Aim 2 will test the hypothesis that ER¿ and ER¿ differentially modulate the activity of spinal dorsal horn neurons to colorectal distention. In electrophysiological experiments, the effects of selective ER agonists (ER¿: PPT; ER¿: DPN) on the response of each of three different phenotypes of CRD-responsive dorsal horn neurons will be determined. Specific Aim 3 will test the hypothesis that ER¿ and ER¿ use different intracellular signaling mechanisms to modulate spinal processing of colorectal stimuli. A multidisciplinary approach will address colocalization of estrogen receptors in the same dorsal horn neurons, expression in glial cells, differential activation of MAPK pathways (ERK, p38 MAPK, JNK) in visceral nociceptive processing and the effect of activation of MAPK pathways on the response of the different phenotypes of visceroceptive dorsal horn neurons. The long-term goal of this project is to understand the role of estrogen receptors in modulating physiological and pathophysiological visceral sensory processing in the spinal cord in order to identify new therapeutic targets. Public Health Relevance

内脏器官引起的疼痛是临床环境中最常见的疼痛形式之一，其中之一患者寻求医疗护理的最常见原因。通常，女性比疼痛更敏感男性和功能性肠病，例如肠易激综合症（IBS），在女性。女性IBS症状的严重程度随着月经周期和内脏敏感性波动大鼠在整个发情周期中波动，表明性腺激素调节伤害性处理内脏刺激。然而，内脏疼痛的激素调节的基础机制很差理解齿。例如，据报道雌激素具有副和抗伤害感作用，使A 对内脏疼痛的激素调节的清晰了解。雌激素受体的两个同工型， er¿，介导了转录调节和雌激素信号在神经系统中的快速影响，有时在相反的方向上。在此应用中，我们将测试这两个受体的假设调节脊髓水平和相互作用的内脏伤害性处理的不同方面这些信号系统中可以对与IBS相关的内脏超敏反应产生影响。利用一个系统级方法我们将解决以下特定目标。特定目标1将检验的假设 [1]雌激素受体调节脊髓水平的结直肠感觉处理，[2] 脊髓中雌激素受体的两个同工型（ER¿和ER？）差异调节内脏运动对结直肠距离（CRD）的响应。作为[1]的子aim，我们将解决负面假设雌二醇不会直接调节结肠影响对CRD的反应。一个多学科电生理，免疫细胞化学和行为方法将用于确定如果在结肠传入DRG神经元中表达Erâ或Erâ，并且在这些受体处的激动剂会调节结肠主要传入的生理学。特定目标2将测试ER¿和ER¿的假设调节脊柱背角神经元对结直肠距离的活性。在电生理实验中，选择性ER激动剂（ER�：PPT;ER¿：DPN）对三种不同的响应的影响将确定CRD反应性背角神经元的表型。特定目标3将检验假设 Erâ和Er¿使用不同的细胞内信号传导机制来调节结直肠的脊柱处理刺激。多学科的方法将解决同一背角中雌激素受体的共定位神经元，在神经胶质细胞中的表达，内脏中MAPK途径的差异激活（ERK，p38 MAPK，JNK）伤害性处理以及MAPK途径激活对不同的响应的影响内脏感受背角神经元的表型。该项目的长期目标是了解角色雌激素受体在调节生理和病理生理的内脏感觉处理中脊髓以识别新的治疗靶标。公共卫生相关性