Genetic dissection of visceral pain pathways

摘要 这项应用的目标是探索内脏疼痛的治疗机会在一套新的细胞 脊髓内的靶点会引起情感性疼痛，而不是反射性防御反应。疼痛来自于 深层组织(如内脏器官、关节、肌肉和骨骼)是最常见和最具破坏性的组织之一。 主要原因包括炎症、神经损伤和肿瘤生长。将临床前洞察力转化为 疼痛的神经生物学对新药的反应一直令人失望。在初步研究中，我的同事们 我已经发现了缺乏进展的一个潜在原因。简而言之，在一系列关于 皮肤疼痛，我们已经确定了一组脊髓上升投射神经元，标记为Tac1-Cre， 对于情绪性的疼痛指示性应对行为是必不可少的，但对于一线的明示-防御行为则是必不可少的 反应。这种在皮肤疼痛水平上的脱节导致了一个可检验的假说。我们建议 对伤害性内脏刺激的反应的情感和防御因素也可以在 脊髓水平。我们的研究计划使用创新的遗传工具来探索对此的可测试预测 假设。我们有两个具体的目标：目标1是测试独特的脊柱基质是 与急性内脏运动反射和情感性内脏疼痛有关。这一预测是基于我们的 初步结果显示，两组脊髓兴奋性神经元(一组是Tac1-Cre神经元)，它们是 由有害的结直肠扩张(CRD)激活，向DISTINCT发送广泛的上升投影 部分重叠的丘脑和中脑核团。同时，我们将测试一组脊椎抑制物 CRD激活的神经元负责控制内脏运动反射和/或情感性疼痛。目标2是测试 预测独特的脊柱底物与炎症性内脏疼痛有关。我们的初步研究已经 确定了两组仅在胃肠道(GI)后才被CRD激活的脊髓兴奋性神经元 炎症，其中之一(标记为VGLUT3-Cre)似乎对介导致敏至关重要 情绪性内脏疼痛。以及其他三组已经被激活的兴奋性神经元 在幼稚的条件下，我们将确定这五组神经元是否传递敏化的内脏运动 反射、情感性内脏疼痛，以及由胃肠道炎症引起的牵涉皮肤疼痛。全 总之，这些研究将为脊椎基质调节不同维度的急性胰腺炎提供新的见解。 和慢性内脏疼痛。

Abstract The goal of this application is to explore therapeutic opportunities for visceral pain in a new set of cellular targets within the spinal cord that will drive affective pain, rather than reflexive-defensive reactions. Pain from deep tissues (e.g. visceral organs, joints, muscles and bones) is among the most prevalent and disruptive. Major causes include inflammation, nerve injury and tumor growth. Translation of preclinical insight into the neurobiology of pain towards new medications has been disappointing. In preliminary studies, my colleagues and I have unmasked one of potential explanations for the lack of progress. Put briefly, in a series of studies on cutaneous pain, we have identified a group of spinal ascending projection neurons, marked by Tac1-Cre, that are essential for affective pain-indicative coping behaviors, but dispensable for first-line nocifensive-defensive reactions. This disconnect at the level of cutaneous pain leads to a testable hypothesis. We propose that affective and defensive elements of the response to noxious visceral stimuli could also be segregated at the level of the spinal cord. Our study plan uses innovative genetic tools to probe testable predictions of this hypothesis. We have two specific aims: Aim 1 is to test the prediction that unique spinal substrates are associated with acute visceromotor reflexes versus affective visceral pain. This prediction is based on our preliminary results, showing that two groups of spinal excitatory neurons (one is Tac1-Cre neurons), which are activated by noxious colorectal distensions (CRD), send extensive ascending projections to distinct, though partially overlapped sets of thalamic and midbrain nuclei. Meanwhile, we will test if a group of spinal inhibitory neurons activated by CRD act to gate visceral motor reflexes and/or affective pain. Aim 2 is to test the prediction that unique spinal substrates are associated with inflammatory visceral pain. Our pilot studies have identified two groups of spinal excitatory neurons that are activated by CRD only after gastrointestinal (GI) inflammation, and one of which (marked by VGLUT3-Cre) appears to be crucial for mediating sensitized affective visceral pain. Together with three other groups of excitatory neurons that are already activated by CRD under naïve conditions, we will determine if these five groups of neurons transmit sensitized visceromotor reflexes, affective visceral pain, as well as the referred cutaneous pain induced by GI inflammation. All together, these studies will provide new insight into spinal substrates mediating different dimensions of acute and chronic visceral pain.