Genetic dissection of visceral pain pathways

内脏疼痛通路的基因剖析

• 批准号: 10379941
• 负责人: QIUFU MA
• 金额: $ 44.52万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379941
• 关键词: Acute; Address; Affect; Affective; Anatomy; Cell Nucleus; Cholecystokinin; Chronic; Clinical; Coping Behavior; Cutaneous; Data; Dimensions; Dissection; Distal; Gastrointestinal tract structure; Genetic; Goals; Inflammation; Inflammatory; Joints; Life; Link; Maps; Mediating; Methods; Midbrain structure; Modeling; Motor; Mus; Muscle; Neurobiology; Neurons; Organ; Pain; Pain Measurement; Pathway interactions; Pharmaceutical Preparations; Physiological; Pilot Projects; Play; Reaction; Rectum; Reflex action; Research Personnel; Resources; Response Elements; Role; SLC17A8 gene; Series; Sodium Dextran Sulfate; Spinal; Spinal Cord; Stimulus; Suggestion; Testing; Thalamic structure; Therapeutic; Tissues; Translations; Visceral; Visceral Afferents; Visceral pain; base; bone; cellular targeting; chronic pain; colorectal distension; deep field survey; drug development; excitatory neuron; feeding; gastrointestinal; genetic approach; improved; inhibitory neuron; innovation; insight; mechanical stimulus; nerve injury; nerve supply; neural circuit; pre-clinical; prevent; response; segregation; success; tool; transmission process; tumor growth

Abstract The goal of this application is to explore therapeutic opportunities for visceral pain in a new set of cellular targets within the spinal cord that will drive affective pain, rather than reflexive-defensive reactions. Pain from deep tissues (e.g. visceral organs, joints, muscles and bones) is among the most prevalent and disruptive. Major causes include inflammation, nerve injury and tumor growth. Translation of preclinical insight into the neurobiology of pain towards new medications has been disappointing. In preliminary studies, my colleagues and I have unmasked one of potential explanations for the lack of progress. Put briefly, in a series of studies on cutaneous pain, we have identified a group of spinal ascending projection neurons, marked by Tac1-Cre, that are essential for affective pain-indicative coping behaviors, but dispensable for first-line nocifensive-defensive reactions. This disconnect at the level of cutaneous pain leads to a testable hypothesis. We propose that affective and defensive elements of the response to noxious visceral stimuli could also be segregated at the level of the spinal cord. Our study plan uses innovative genetic tools to probe testable predictions of this hypothesis. We have two specific aims: Aim 1 is to test the prediction that unique spinal substrates are associated with acute visceromotor reflexes versus affective visceral pain. This prediction is based on our preliminary results, showing that two groups of spinal excitatory neurons (one is Tac1-Cre neurons), which are activated by noxious colorectal distensions (CRD), send extensive ascending projections to distinct, though partially overlapped sets of thalamic and midbrain nuclei. Meanwhile, we will test if a group of spinal inhibitory neurons activated by CRD act to gate visceral motor reflexes and/or affective pain. Aim 2 is to test the prediction that unique spinal substrates are associated with inflammatory visceral pain. Our pilot studies have identified two groups of spinal excitatory neurons that are activated by CRD only after gastrointestinal (GI) inflammation, and one of which (marked by VGLUT3-Cre) appears to be crucial for mediating sensitized affective visceral pain. Together with three other groups of excitatory neurons that are already activated by CRD under naïve conditions, we will determine if these five groups of neurons transmit sensitized visceromotor reflexes, affective visceral pain, as well as the referred cutaneous pain induced by GI inflammation. All together, these studies will provide new insight into spinal substrates mediating different dimensions of acute and chronic visceral pain.

抽象的 该应用的目的是在一组新的细胞中探索内脏疼痛的热机会 脊髓内的靶标会导致情感疼痛，而不是反身防御反应。疼痛 深组织（例如内脏器官，关节，肌肉和骨骼）是最普遍，破坏性的。 主要原因包括注射，神经损伤和肿瘤生长。将临床前洞察力翻译成 对新药物疼痛的神经生物学令人失望。在初步研究中，我的同事 而且我揭露了缺乏进步的潜在解释之一。简而言之 皮肤疼痛，我们已经确定了一组脊柱上升投影神经元，标有Tac1-cre的标志 对于情感疼痛指示的应对行为至关重要，但对于一线防御性来说是必不可少的 反应。在皮肤疼痛水平上断开连接导致可检验的假设。我们提出了这一点 对有害内脏刺激的反应的情感和防御性元素也可以在 脊髓的水平。我们的研究计划使用创新的遗传工具来探测可检验的预测 假设。我们有两个具体的目标：目标1是测试独特的脊柱底物的预测 与急性内脏反射与情感内脏疼痛有关。这个预测是基于我们的 初步结果表明，两组脊柱兴奋性神经元（一个是TAC1-CRE神经元），它们是 通过有害的结直肠延伸（CRD）激活，将广泛的上升项目发送到不同 部分重叠的丘脑和中脑核。同时，我们将测试一组脊柱抑制 由CRD ACT激活的神经元为栅极内脏运动反射和/或情感疼痛。目标2是测试 预测独特的脊柱底物与炎症内脏疼痛有关。我们的试点研究有 仅在胃肠道（GI）后才鉴定出两组脊柱兴奋神经元。 炎症，其中一种（由VGLUT3-CRE标记）对于介导敏感的 情感内脏疼痛。以及其他三组兴奋神经元已经激活 CRD在幼稚的条件下，我们将确定这五组神经元是否传递敏感的内脏运动 反射，情感内脏疼痛以及胃肠道炎症引起的推荐皮肤疼痛。全部 总之，这些研究将为介导急性不同维度的脊柱底物提供新的见解 和慢性内脏疼痛。