Neurochemical mechanisms of visceral pain

内脏痛的神经化学机制

• 批准号: 7937810
• 负责人: RICHARD J Traub
• 金额: $ 32.48万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937810
• 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' 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

DESCRIPTION (provided by applicant): 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, ER1 and ER2, 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 (ER1 and ER2) 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 ER1 or ER2 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 ER1 and ER2 differentially modulate the activity of spinal dorsal horn neurons to colorectal distention. In electrophysiological experiments, the effects of selective ER agonists (ER1: PPT; ER2: 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 ER1 and ER2 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: Most chronic pain syndromes are more prevalent in one sex, the majority being in women. Symptoms in many of these conditions fluctuate with the menstrual cycle suggesting modulation by gonadal hormones. Using colorectal distention to model pain from the viscera, we will test the hypothesis that the two isoforms of the estrogen receptor, located in the spinal cord, differentially modulate visceral sensitivity. The long term goal of these studies is to identify novel therapeutic interventions for the treatment of visceral hypersensitivity associated with functional bowel disorders.

描述（由申请人提供）：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，也是患者寻求医疗护理的最常见原因之一。通常，女性对疼痛的敏感性比男性和功能性肠道疾病（例如肠易激综合症（IBS））的敏感性高2-3倍。女性IBS症状的严重程度随着大鼠的月经周期和内脏敏感性的波动，在整个发情周期中波动，表明性腺激素调节内脏刺激的伤害感受性处理。然而，对内脏疼痛的激素调节的基础机制知之甚少。例如，据报道，雌激素具有副作用和抗伤心作用，使人们对内脏疼痛的激素调节有清晰的了解。雌激素受体ER1和ER2的两个同工型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2个受体在脊髓水平上调节内脏伤害性处理的不同方面的假设，这些信号系统的相互作用可以对与IBS相关的内脏性超敏。利用系统级方法，我们将解决以下特定目标。具体目标1将测试[1]雌激素受体在脊髓水平上调节结直肠感觉处理的假设，并且[2]脊髓中雌激素受体（ER1和ER2）的两个同工型在差异调节了对结直肠沟通（CRD）的内脏响应（CRD）。作为[1]的子aim，我们将解决雌二醇不会直接调节结肠传入对CRD的响应的阴性假设。多学科的电生理，免疫细胞化学和行为方法将用于确定在结肠传入的DRG神经元中表达ER1或ER2是否表达，以及这些受体的激动剂是否会调节结肠初级传入的生理学。具体目标2将检验以下假设：ER1和ER2差异地调节脊柱背角神经元对结直肠差的活性。在电生理实验中，将确定选择性ER激动剂（ER1：PPT; ER2：DPN）的影响对CRD反应性背角神经元的三种不同表型的响应。具体目标3将检验以下假设：ER1和ER2使用不同的细胞内信号传导机制来调节结直肠刺激的脊柱加工。多学科的方法将解决同一背角神经元中雌激素受体的共定位，在内脏伤害感受器处理中MAPK途径的差异激活（ERK，p38 MAPK，JNK）的差异激活以及MAPK途径激活的效果MAPK途径对不同现象型霍恩的响应的效果。该项目的长期目标是了解雌激素受体在调节脊髓中生理和病理生理的内脏感觉处理中的作用，以鉴定新的治疗靶标。 公共卫生相关性： 大多数慢性疼痛综合征在一种性别中更为普遍，大多数在女性中。在许多情况下，随着月经周期的症状波动，表明性腺激素调节。使用结直肠扩张来模拟内脏的疼痛，我们将检验以下假设：位于脊髓中的雌激素受体的两个同工型对内脏敏感性进行差异调节。这些研究的长期目标是确定与功能性肠疾病相关的内脏超敏反应治疗的新型治疗干预措施。