Comparative mapping of functionally distinct visceral afferent nociceptive pathways

内脏疼痛是一种使人虚弱且知之甚少的疾病，也是寻求医疗服务的常见原因。 请注意。与躯体疼痛相比，人们对内脏疼痛通路的了解要少得多。取得的进展 这一区域一直很慢，因为内脏疼痛更难测量，大多数内脏传入 神经并不参与疼痛，而是参与自主调节，它们的遗传身份往往未知。疼痛 可以从某些器官(如食道、胃、输尿管、结肠)诱发，但不能从其他器官(如肝脏、 脾、肺)，尽管所有内脏器官都由生物化学相似的传入神经支配。 我们的中心假设是，来自引起疼痛的器官的伤害性通路仅与 中枢痛觉通路与来自其他器官的伤害性通路的比较。因此，彻底比较 产生疼痛的器官与不产生疼痛的器官之间的传入通路将提供 识别传入的内脏亚群和脊髓通路，它们专门调节内脏疼痛。然而， 这样的任务需要以前没有的策略来分析周围神经的反应性 基因定义的内脏传入亚集的终末，并可靠地追踪它们的中枢联系。我们 已经开发出一系列最先进的技术，允许对单个传入子集进行映射 由同时来自两个器官的两个基因的重合来定义的。我们的方法将跟踪 DRG传入自身，或这些特定子集下游的中央通路(连接体)。 联合功能评价原位检测背根神经节传入亚群伤害性状态 GCaMP6成像，这些方法将首次提供激活的中央通路的知识 通过独特的基因定义的伤害性亚集。我们的合作团队由泰勒-克拉克博士组成 和Kollarik，内脏伤害性传入的专家，病毒学家滕和恩格尔博士，以及迪肯森博士， 内脏和躯体感觉疼痛的脊椎和棘上通路专家。我们将致力于以下工作 具体目标：目标1：定位负责内脏痛的小鼠胸腔传入通路 辣椒素敏感(TRPV1+)DRG伤害性感受器的激活。目标2：绘制多肽能与 非肽能伤害性感受器在胸廓传入通路中的作用 辣椒素敏感(TRPV1+)DRG伤害性感受器。目的3：MAP小鼠TRPV1阴性的胸部传入 小路。翻译目标4：在大鼠和人组织中定位TRPV1+和Tac1+的食道传入。我们 期望识别和绘制支配食道的特定DRG传入亚群的中央通路 还有肺。此外，我们希望识别的路径连接到疼痛中心，这是唯一的 食道(与肺)的传入神经将是特异性调节内脏痛的候选神经。我们的 对小鼠、大鼠和人类组织的研究将增加我们对内脏疼痛的理解。

Visceral pain is a debilitating and poorly understood condition that is a common cause for seeking medical attention. In comparison to somatic pain, much less is known about the visceral pain pathways. Progress in this area has been slow because visceral pain is more difficult to measure, the majority of visceral afferent nerves are involved not in pain but in autonomic regulation, and their genetic identities are often unknown. Pain can be evoked from some organs (e.g. esophagus, stomach, ureter, colon) but not from others (e.g. liver, spleen, lung), despite the fact that all visceral organs are innervated by biochemically similar afferent nerves. Our central hypothesis is that nociceptive pathways from pain-evoking organs are exclusively connected to central pain pathways compared to nociceptive pathways from other organs. Thus, a thorough comparison of afferent pathways from the organs which produce pain vs. those which do not produce pain will provide the identity the afferent visceral subsets and spinal pathways which specifically mediate visceral pain. However, such task requires previously unavailable strategies to analyze the responsiveness of peripheral nerve terminals of genetically-defined visceral afferent subsets, and to reliably trace their central connections. We have developed a battery of state-of-the-art techniques that allow for the mapping of individual afferent subsets defined by the coincidence of two genes from two organs simultaneously. Our approach will trace either the DRG afferents themselves, or the central pathways (connectomes) downstream of these specific subsets. Combined with functional assessment of the nociceptive status of DRG afferent subsets in situ by using GCaMP6 imaging, these approaches will for the first time provide knowledge of the central pathways activated by unique genetically-defined nociceptive subsets. Our collaborative team is comprised of Drs. Taylor-Clark and Kollarik, experts in visceral nociceptive afferents; Drs. Teng and Engel, virologists; and Dr. Dickenson, an expert in spinal and supraspinal pathways of visceral and somatosensory pain. We will pursue the following specific aims: Aim 1: Map the murine thoracic afferent pathways responsible for visceral pain evoked by the activation of capsaicin-sensitive (TRPV1+) DRG nociceptors. Aim 2: Map the contribution of peptidergic vs. non-peptidergic nociceptors to thoracic afferent pathways responsible for visceral pain evoked by the activation of capsaicin-sensitive (TRPV1+) DRG nociceptors. Aim 3: Map murine TRPV1-negative thoracic afferent pathways. Translational aim 4: Map TRPV1+ and Tac1+ esophageal afferents in rat and human tissue. We expect to identify and map the central pathways of specific DRG afferent subsets innervating the esophagus and lung. Furthermore, we expect the identified pathways connected to pain centers that are unique to esophageal (vs. lung) afferent innervation will be candidates for specifically mediating visceral pain. Our studies in mouse, rat and human tissue will increase our understanding of visceral pain.