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。许多评估这种网络的研究集中在三叉神经伤害性感觉的外周机制以及三叉神经和脊髓伤害性感觉处理之间的同源性。这项工作的扩展目标是研究三叉神经中央终末(三叉神经传入)和三叉神经脊束核尾侧核(VC)神经元之间突触传递的细胞机制。三叉神经脊束核尾侧核是一个脑干区，与面部的伤害性加工有关。我们推测，Vc内三叉神经传入和神经元的突触连接是由谷氨酸作用于非NMDA和NMDA受体介导的，并可能受到选择性离子通道的调节，特别是瞬时受体电位香草样物质1(TRPV1)。我们还认为，这些功能联系可能具有明显的解剖学特征。NMDA受体和非NMDA受体均可在Vc内观察到，但它们在该区域的兴奋性突触传递中的作用尚不清楚。TRPV1在三叉神经细胞的外周和中央终末均有表达，TRPV1的上调与异常疼痛密切相关。在外周方面，TRPV1被广泛地描述为伤害性信息的分子转导；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用体外电生理技术检测三叉神经传入和Vc神经元的功能连接性，评估突触潜伏期变异性作为突触顺序的指标，NMDA和非NMDA通道上谷氨酸介导的反应，以及TRPV1是否以脑干突触传递(如NTS)为模型调节Vc内的谷氨酸能反应。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独的三叉神经传入，中央TRPV1的化学激活可以诱导可测量的反应。目的2，确定与突触潜伏期变异相关的Vc神经元的形态特征，并评价三叉神经传入与Vc神经元之间与TRPV1的解剖联系。这些结果将与目标1的发现相结合，以提供对三叉神经传入和VC神经元亚群之间的关系以及突触传递的细胞机制的更具体的理解。这些结果将为神经网络提供重要的、补充的解剖学和功能信息，这些神经网络将感觉信息从面部传递到大脑，包括TRPV1在三叉神经痛通路中的作用，并确定神经可塑性和颅面疼痛调制的潜在机制。

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.