Determine Functions of Mammalian Touch-sensing Neurons in Chronic Pain

确定哺乳动物触觉神经元在慢性疼痛中的功能

基本信息

批准号：
10210302
负责人：
Wenqin Luo
金额：
$ 46.19万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10210302
关键词：
Acute Acute Pain Affect Age Amyloid beta-Protein Anatomy Behavior Cannulas Cations Chronic Data Electric Stimulation Fiber Floor Foundations Future Histology Inflammation Injury Intervention Lasers Lateral Lead Lesion Light Literature Lumbar spinal cord structure Massage Mechanoreceptors Mediating Modality Modeling Mus Neurons Neurostimulation procedures of spinal cord tissue Nociception Optics Outcome Pain Pathway interactions Peripheral Physiological Physiology Play Population Property Protocols documentation Reading Reflex action Reporter Research Research Personnel Role Skin Slice Specificity Speed Spinal Spinal Cord Spinal Ganglia Stimulus Structure of trigeminal ganglion Synapses System Testing Touch sensation Transgenic Mice Wireless Technology Work awake base behavior change behavioral outcome chronic pain chronic painful condition computational neuroscience dorsal column experimental study histological studies imaging modality implantable device improved in vivo injured insight loss of function mechanical allodynia mouse genetics neural circuit novel optogenetics pain behavior pain sensation recruit response somatosensory spinal nerve posterior root synaptic inhibition

项目摘要

The mammalian touch-sensing afferents, Aβ low-threshold mechanoreceptors (LTMRs), have long been pro- posed to be important players in modulating nociceptive pathways. However, the exact roles of Aβ LTMRs in chronic pain are still under debate. Aiming to incorporating the known anatomy of Aβ LTMRs and existing con- flicting results, we hypothesize that in chronic pain conditions, peripheral activation of Aβ LTMRs innervating the affected region triggers pain through dis-inhibited feedforward circuits, whereas dorsal column activation recruits Aβ LTMRs innervating both affected and non-affected regions, which could block activities of affected Aβ LTMRs and/or pain pathways through lateral inhibition. To specifically test this idea, we will generate transgenic mice in which channelrhodopsin will be specifically expressed in Aβ LTMRs and examine their histology (Aim 1a) and physiological properties (Aims 1b) at base-line and chronic pain conditions. We will then take advantage of the spatial and temporal precision of optogenetics and stimulate Aβ LTMRs peripherally in the skin or centrally in the spinal cord dorsal column at baseline and various chronic pain conditions to compare their behavioral outcomes (Aim 2). Finally, we will use spinal cord slice recordings to elucidate the underlying circuit mechanisms (Aim 3). We will combine dorsal root electrical stimulation and optical stimulation to activate Aβ LTMRs locally from a given level or broadly to determine lateral inhibition existing among Aβ LTMRs at baseline and chronic pain conditions. We will also determine whether this lateral inhibition could modulate the local nociceptive circuits affected by chronic inflamma- tion/injury. Collectively, our results are expected to establish a new model of how crosstalk between modalities (touch and nociceptive pathways) and within one modality (Aβ LTMRs from different spinal cord segments) work together to modulate pain sensation. This model would not only explain the complicated functions of Aβ LTMRs in chronic pain but also provide novel insights for pain pathway intervention in the future. Our assem- bled team is well suited to complete these aims, utilizing combined expertise in mouse genetics and Aβ LTMRs (PI Luo) and physiology and computational neuroscience with the mammalian somatosensory system (co- investigator O’Connor).

哺乳动物的触觉传入神经 Aβ 低阈值机械感受器 (LTMR) 长期以来一直支持然而，Aβ LTMR 在调节伤害性通路中发挥着重要作用。慢性疼痛仍在争论中，旨在将 Aβ LTMR 的已知解剖结构和现有的缺点结合起来。与结果相矛盾的是，我们追踪到，在慢性疼痛情况下，Aβ LTMR 的外周激活神经支配受影响的区域通过解除抑制的前馈回路触发疼痛，而背柱激活募集 Aβ LTMR 来支配受影响和未受影响的区域，这可能会阻止受影响区域的活动 Aβ LTMR 和/或通过侧向抑制的疼痛通路为了具体测试这一想法，我们将生成转基因小鼠，其中通道视紫红质将在 Aβ LTMR 中特异性表达，并检查其组织学（目标 1a）和生理特性（目标 1b）。然后，我们将利用光遗传学的空间和时间精度，刺激皮肤外周或脊髓中央的 Aβ LTMR。最后，我们将使用脊髓切片记录来阐明潜在的回路机制（目标 3）。从给定水平局部激活 Aβ LTMR 或广泛激活 Aβ LTMR 以确定我们还将确定基线和慢性疼痛条件下 Aβ LTMR 中存在的侧向抑制。这种侧向抑制是否可以调节受慢性炎症影响的局部伤害性回路总的来说，我们的结果有望建立一个关于模式之间如何串扰的新模型。（触摸和伤害感受通路）和一种模式内（来自不同脊髓节段的 Aβ LTMR）该模型不仅可以解释 Aβ 的复杂功能。 LTMR 在治疗慢性疼痛的同时也为未来的疼痛通路干预提供了新的见解。 bled 团队利用小鼠遗传学和 Aβ LTMR 方面的综合专业知识，非常适合完成这些目标（皮罗）和生理学和计算神经科学与哺乳动物体感系统（共同调查员奥康纳）。