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 该应用的目标是探索一组新的细胞中内脏疼痛的治疗机会 脊髓内的目标会引起情感疼痛，而不是反射性防御反应。 深层组织（例如内脏器官、关节、肌肉和骨骼）是最普遍和最具破坏性的。 主要原因包括炎症、神经损伤和肿瘤生长。 在初步研究中，我的同事们对新药物的疼痛神经生物学结果感到失望。 简而言之，我在一系列研究中揭示了缺乏进展的一个可能的解释。 为了缓解皮肤疼痛，我们鉴定了一组脊髓上行投射神经元，以 Tac1-Cre 为标记， 对于情感性疼痛指示性应对行为至关重要，但对于一线伤害性防御来说是可有可无的 皮肤疼痛水平上的这种脱节导致了一个可检验的假设。 对有害内脏刺激反应的情感和防御成分也可以在 我们的研究计划使用创新的遗传工具来探索可测试的预测。 我们有两个具体目标：目标 1 是检验独特脊柱基质的预测。 与急性内脏运动反射与情感性内脏疼痛相关。这一预测是基于我们的。 初步结果显示，两组脊髓兴奋性神经元（一组是 Tac1-Cre 神经元），分别是 由有害的结直肠扩张 (CRD) 激活，但会向不同的部位发送广泛的上升投射 同时，我们将测试一组部分重叠的丘脑和中脑核团是否具有抑制性。 CRD 激活的神经元会控制内脏运动反射和/或情感疼痛。目标 2 是测试 我们的初步研究预测独特的脊柱基质与炎症性内脏疼痛有关。 确定了两组脊髓兴奋性神经元，这些神经元仅在胃肠道 (GI) 后被 CRD 激活 炎症，其中之一（由 VGLUT3-Cre 标记）似乎对于介导敏化至关重要 情感性内脏疼痛以及其他三组兴奋性神经元已经被激活。 在初始条件下进行 CRD，我们将确定这五组神经元是否传递敏化内脏运动 反射、情感性内脏疼痛以及胃肠道炎症引起的皮肤疼痛。 总之，这些研究将为介导不同维度急性发作的脊髓基质提供新的见解。 和慢性内脏疼痛。