Primary Afferent Transmission in the Trigeminal Dorsal Horn

描述（由申请人提供）：了解驱动颅面疼痛的神经网络内的解剖和生理关系是开发有效治疗方法的关键一步。许多研究评估这种网络集中在三叉神经伤害性感受的外周机制和三叉神经和脊髓伤害性感受加工之间的同源性。这项工作的扩展目标是研究三叉神经（三叉神经传入）的中央末梢和位于三叉神经脊束核尾侧（Vc），脑干区域涉及的伤害性处理的面部神经元之间的突触传递的细胞机制。我们假设，突触连接的个别三叉神经传入和神经元的Vc是由谷氨酸介导的非NMDA和NMDA受体的作用，并可能通过选择离子通道，特别是瞬时受体电位香草酸1型（TRPV 1）调制。我们还认为，这些功能性连接可能具有独特的解剖学特征。在Vc中观察到NMDA和非NMDA受体，尽管它们在该区域介导兴奋性突触传递中的作用尚不明确。TRPV 1在三叉神经元的外周和中枢末端均有表达，TRPV 1的上调与异常疼痛密切相关。在外周，TRPV 1已被广泛地表征为伤害性信息的分子转导器;然而，中枢运输的TRPV 1通道在疼痛处理中的作用仍不清楚。目的1将确定三叉神经传入和Vc神经元的功能连接与体外电生理技术评估：突触潜伏期变异性作为衡量突触秩序，谷氨酸介导的反应，在NMDA和非NMDA通道，如果TRPV 1调制mammatergic反应在Vc使用脑干突触传递（如NTS）作为一个模型。初步数据表明，可以使用突触潜伏期变异性的测量来识别单个三叉神经传入，并且中央TRPV 1的化学激活诱导可测量的反应。目的2，将确定与突触潜伏期变异性相关的Vc神经元的形态学特征，并评估三叉神经传入和Vc神经元之间关于TRPV 1的解剖连接。这些结果将与目标1的结果相结合，以更具体地了解三叉神经传入和Vc神经元亚群之间的关系以及突触传递的细胞机制。这些结果将提供重要的，互补的解剖学和功能信息的神经网络，中继感觉信息从面部到大脑，包括TRPV 1在三叉神经疼痛通路中的作用，并确定神经可塑性和颅面疼痛的调制的潜在机制。

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.