Primary Afferent Transmission in the Trigeminal Dorsal Horn

三叉神经背角的初级传入传输

• 批准号: 8253418
• 负责人: Tally Marie Milnes
• 金额: $ 4.92万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253418
• 关键词: Afferent Neurons; American; Anatomy; Automobile Driving; Axon; Behavioral; Biological Neural Networks; Biomedical Research; Brain; Brain Stem; Capsaicin; Cations; Cells; Cephalic; Chemicals; Complement; Confocal Microscopy; Cornea; Craniofacial Pain; Data; Depressed mood; Detection; Dura Mater; Electric Stimulation; Electrophysiology (science); Esthesia; Face; Face Processing; Fiber; Frequencies; Future; Glutamate Receptor; Glutamates; Goals; In Vitro; Individual; Investigation; Ion Channel; Label; Laboratories; Measurable; Measures; Mediating; Modeling; Molecular; Mono-S; Morphology; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; National Institute of Dental and Craniofacial Research; Nature; Neuronal Plasticity; Neurons; Neurosciences; Neurotransmitters; Nociception; Nociceptors; Nucleus solitarius; Organ; Orofacial Pain; Pain; Pain Research; Pathway interactions; Peripheral; Physiological; Population; Positioning Attribute; Process; Reporting; Research; Role; Sensory; Slice; Spinal; Stimulus; Structure; Structure of trigeminal nerve spinal tract nucleus; Synapses; Synaptic Transmission; System; Techniques; Testing; Thalamic structure; Therapeutic; Tissues; Tooth structure; Training; Transducers; Trigeminal Neuralgia; Trigeminal System; Trigeminal nerve structure; Up-Regulation; Vanilloid; Vertebral column; Vesicle; Visceral; Work; base; biocytin; career; dorsal horn; orofacial; pain behavior; patch clamp; receptor; reconstruction; relating to nervous system; response; skills; therapeutic target; trafficking; transmission process

DESCRIPTION (provided by applicant): Understanding of anatomical and physiological relationships within the neural networks driving craniofacial pain is a key step in developing effective therapeutic treatments. Many studies evaluating such networks focus on peripheral mechanisms of trigeminal nociception and on homologies between trigeminal and spinal nociceptive processing. The extended goal of this work is to investigate the cellular mechanisms underlying synaptic transmission between the central terminals of the trigeminal nerve (trigeminal afferents) and neurons located in the spinal trigeminal nucleus caudalis (Vc), a brainstem region implicated in nociceptive processing for the face. We hypothesize that synaptic connectivity of individual trigeminal afferents and neurons in the Vc is mediated by glutamate acting at non-NMDA and NMDA receptors and may be modulated by select ion channels, specifically the Transient Receptor Potential Vanilloid type 1 (TRPV1). We also believe that these functional connections may have distinct anatomical features. Both NMDA and non-NMDA receptors are observed in Vc, although their roles in mediating excitatory synaptic transmission in this region are ill-defined. TRPV1 is expressed on both peripheral and central termini of trigeminal neurons and upregulation of TRPV1 is closely associated with abnormal pain. Peripherally, TRPV1 has been characterized extensively as a molecular transducer of nociceptive information; however, the roles of centrally trafficked TRPV1 channels in pain processing remain unclear. Aim 1 will determine the functional connectivity of trigeminal afferents and Vc neurons with in vitro electrophysiological techniques assessing: synaptic latency variability as a measure of synaptic order, glutamate-mediated responses at NMDA and non-NMDA channels, and if TRPV1 modulates glutamatergic responses in Vc using brainstem synaptic transmission (e.g. NTS) as a model. Preliminary data demonstrate that individual trigeminal afferents can be identified using measures of synaptic latency variability, and chemical activation of central TRPV1 induces measurable responses. Aim 2, will determine the morphological features of Vc neurons related to synaptic latency variability and evaluate the anatomical connectivity between trigeminal afferents and Vc neurons with respect to TRPV1. The results will be integrated with findings from Aim 1 to provide a more specific understanding of the relationship between trigeminal afferent and Vc neuron subpopulations and the cellular mechanisms underlying synaptic transmission. These results will provide important, complementary anatomical and functional information about the neural networks that relay sensory information from the face to the brain, including the role of TRPV1 in the trigeminal pain pathway, and identify potential mechanisms for both neural plasticity and modulation of craniofacial pains. PUBLIC HEALTH RELEVANCE: According to the National Institute of Dental and Craniofacial Research's Panel on Pain Research 2003, 22% of the American population reports having orofacial pain, the most common type of craniofacial pain. Facial tissues are innervated by neurons which comprise the trigeminal nerve. These neurons branch both peripherally to the face and centrally to the brain creating a relay network for processing of nociceptive sensory information. The current proposal seeks to understand the cellular mechanisms driving neural integration of pain sensations transmitted from the face to the brain with the potential to identify therapeutic targets for modulation of craniofacial pain.

描述（由申请人提供）：对驱动颅面疼痛的神经网络中解剖学和生理关系的理解是开发有效治疗治疗的关键步骤。许多评估此类网络的研究集中在三叉神经受伤的外围机制以及三叉神经和脊柱伤害性处理之间的同源性上。这项工作的扩展目标是研究三叉神经（三叉神经传统）的中央末端之间的突触传播的细胞机制和位于脊柱三叉神经核（VC）中的神经元，这是脑干区域，这是脑干区域，与面部的伤害性处理有关。我们假设VC中单个三叉神经传统和神经元的突触连通性是由作用于非NMDA和NMDA受体作用的谷氨酸介导的，并且可以通过精选离子通道进行调节，具体是瞬态受体受体电位vanilloid Type 1型（TRPV1）。我们还认为，这些功能连接可能具有不同的解剖特征。在VC中观察到NMDA和非NMDA受体，尽管它们在该区域中介导兴奋性突触传播中的作用却很差。 TRPV1在三叉神经元的外围和中央末端都表达，TRPV1的上调与异常疼痛密切相关。在外围，TRPV1已被广泛地作为伤害感受信息的分子传感器。但是，中心运输的TRPV1通道在疼痛处理中的作用尚不清楚。 Aim 1 will determine the functional connectivity of trigeminal afferents and Vc neurons with in vitro electrophysiological techniques assessing: synaptic latency variability as a measure of synaptic order, glutamate-mediated responses at NMDA and non-NMDA channels, and if TRPV1 modulates glutamatergic responses in Vc using brainstem synaptic transmission (e.g. NTS) as a model.初步数据表明，可以使用突触潜伏期可变性的度量来鉴定单个三叉神经传入，并且中央TRPV1的化学激活可诱导可测量的响应。 AIM 2将确定与突触潜伏期变异性相关的VC神经元的形态特征，并评估三叉神经传导物与VC神经元相对于TRPV1的解剖连通性。结果将与AIM 1的发现集成在一起，以更具体地了解三叉神经传入和VC神经元亚群以及突触传播的细胞机制之间的关系。这些结果将提供有关神经网络的重要，互补的解剖学和功能信息，这些信息将感官信息从面部转移到大脑，包括TRPV1在三叉神经疼痛途径中的作用，并确定有关神经可塑性和颅面疼痛调节的潜在机制。 公共卫生相关性：根据国家牙科和颅面研究研究所的疼痛研究小组，2003年，美国人群中有22％的人口报告具有口面疼痛，这是最常见的颅面疼痛类型。面部组织由包含三叉神经的神经元支配。这些神经元在外围分支到面部和集中到大脑，创建了一个继电器网络，用于处理伤害感性的感官信息。当前的建议旨在了解驱动从面部到大脑传播的疼痛感觉神经整合的细胞机制，并有可能识别调节颅面疼痛的治疗靶标。