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中的解剖和生理关系是开发有效治疗方法的关键步骤。许多评估这些网络的研究集中在三叉神经伤害感觉的外周机制以及三叉神经和脊髓伤害感觉加工之间的同源性。这项工作的扩展目标是研究三叉神经中央末端（三叉神经传入事件）和位于三叉神经脊髓尾核（Vc）的神经元之间突触传递的细胞机制，这是一个涉及面部伤害性加工的脑干区域。我们假设Vc中单个三叉神经传入事件和神经元的突触连通性是由作用于非NMDA和NMDA受体的谷氨酸介导的，并可能通过特定的离子通道，特别是瞬时受体电位香草样蛋白1 （TRPV1）进行调节。我们还认为，这些功能性连接可能具有不同的解剖学特征。在Vc中可以观察到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。TRPV1在三叉神经外周和中枢端均有表达，TRPV1的上调与异常疼痛密切相关。在外周，TRPV1被广泛地描述为伤害性信息的分子换能器；然而，中枢运输的TRPV1通道在疼痛处理中的作用尚不清楚。目的1将通过体外电生理技术评估三叉神经传入事件和Vc神经元的功能连通性：突触潜伏期变异性作为突触顺序的测量，谷氨酸介导的NMDA和非NMDA通道的反应，以及TRPV1是否以脑干突触传递（如NTS）为模型调节Vc中的谷氨酸反应。初步数据表明，个体三叉神经传入事件可以通过突触潜伏期变异性来识别，中枢TRPV1的化学激活可以诱导可测量的反应。目的2，将确定与突触潜伏期变异相关的Vc神经元的形态学特征，并评估三叉神经传入事件与Vc神经元之间关于TRPV1的解剖连通性。这些结果将与Aim 1的发现相结合，以提供对三叉神经传入和Vc神经元亚群之间关系以及突触传递背后的细胞机制的更具体理解。这些结果将为从面部到大脑传递感觉信息的神经网络提供重要的、互补的解剖学和功能信息，包括TRPV1在三叉神经疼痛通路中的作用，并确定颅面疼痛的神经可塑性和调节的潜在机制。

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.