Genetic dissection of visceral pain pathways

摘要 本申请的目的是探索在一组新的细胞中治疗内脏疼痛的机会。 脊髓内的目标，将驱动情感疼痛，而不是反射性防御反应。疼痛 深部组织（例如内脏器官、关节、肌肉和骨骼）是最普遍和最具破坏性的。 主要原因包括炎症、神经损伤和肿瘤生长。将临床前见解转化为 疼痛神经生物学对新药的研究一直令人失望。在初步研究中，我的同事们 我发现了缺乏进展的一个潜在原因简而言之，在一系列关于 在皮肤疼痛中，我们已经确定了一组脊髓上行投射神经元，标记为Tac 1-Cre， 是情感性疼痛指示应对行为所必需的，但对一线伤害防御-防御行为来说是必要的。 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设。我们建议 对伤害性内脏刺激的反应的情感和防御成分也可以在 脊髓水平。我们的研究计划使用创新的遗传工具来探索可测试的预测， 假说.我们有两个具体目标：目标1是测试独特的脊髓基质是 与急性内脏反射和情感性内脏痛有关。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（一个是Tac 1-Cre神经元），这是 由有害性结直肠扩张（CRD）激活，发送广泛的上行投射到不同的，虽然 部分重叠的丘脑和中脑核。同时，我们将测试一组脊髓抑制剂 由CRD激活的神经元用于控制内脏运动反射和/或情感疼痛。目标2是测试 预测独特的脊髓基质与炎性内脏痛相关。我们的试点研究 确定了两组脊髓兴奋性神经元，仅在胃肠道（GI）后被CRD激活， 炎症，其中之一（标记为VGLUT 3-Cre）似乎是至关重要的介导敏化 情感性内脏痛与其他三组已经被激活的兴奋性神经元一起 CRD在幼稚条件下，我们将确定这五组神经元是否传递致敏内脏神经元。 反射、情感性内脏痛以及由GI炎症引起的牵涉性皮肤痛。所有 总之，这些研究将提供新的见解脊髓基质介导不同层面的急性 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.