Characterization and Plasticity of Visceral Nociceptors

描述(申请人提供)：由内脏感觉神经元引起的病理性疼痛是器官功能障碍的组成部分，在没有任何明显的结构异常(例如肠易激综合征)的情况下可能会发生。内脏疼痛也是许多慢性病(如与克罗恩氏病有关的疼痛)导致衰弱的重要原因。内脏感觉生物学的长期目标是确定这些持续性疼痛状态的原因，并开发专门针对这些情况的治疗方法。最近，在低估躯体疼痛方面取得了重大进展。这在很大程度上是由于分子和遗传模型的发展，这些模型允许比以前可能的更高水平的分辨率。众所周知，内脏传入与躯体传入非常不同[26]。然而，如果用于检测躯体伤害性感觉的技术可以适用于内脏感觉系统，那么在阐明内脏疼痛的基本机制方面也可以取得同样重大的进展。为此，本实验结合了行为学、解剖学、生理学和遗传学的方法来研究小鼠的内脏传入。将使用一种新的“体外”生理学范式，保留整个感觉神经元，包括它与器官(在这种情况下是结肠)的外周连接，以及它与脊髓的中心连接。这项应用有四个具体的目的：第一，确定内脏传入投射到不同的腹部和盆腔器官的异质性。第二个目标是使用体外准备来确定单个内脏感觉神经元的综合表型(CP)。CP包括对中枢和外周突起的解剖学描述、神经化学特征，以及对动作电位形状、传导速度和反应特性的分析(例如阈值、适当的刺激类型)。这些信息对于第三个目标至关重要，该目标是确定不同群体的内脏传入神经元(根据CP识别)对侮辱的反应。对于第四个目的，我们将在缺乏瞬时受体潜力香草素亚家族受体1(TRPV1，以前称为VR1)的小鼠中重复这些研究，以确定是否类似于躯体传入，该通道是发展超敏反应所必需的。

DESCRIPTION (provided by applicant): Pathological pain arising from visceral sensory neurons is integral to organ dysfunction and can occur in the absence of any obvious structural abnormalities (e.g. irritable bowel syndrome). Visceral pain also contributes significantly to the debilitating nature of many chronic diseases (e.g. pain associated with Crohns's disease). The long-term goal in visceral sensory biology is to identify the causes of these persistent pain states and to develop therapies that specifically target these conditions. Recently, significant advances have been made in understating somatic pain. In large part, this is due to the development of molecular and genetic models that allow a greater level of resolution than has been previously possible. It is well established that visceral afferents are very different from somatic afferents [26]. However, if the techniques used to examine somatic nociception could be adapted for visceral sensory systems, equally significant progress could be made to elucidate basic mechanisms underlying visceral pain. To that end, the present experiments combine behavioral, anatomical, physiological and genetic approaches to study visceral afferents in the mouse. A novel "ex vivo" physiology paradigm that preserves the entire sensory neuron, including its peripheral connection to the organ (in this case the colon) and its central connection to the spinal cord, will be used. This application has 4 specific aims: The first is to determine the heterogeneity of visceral afferents projecting to different abdominal and pelvic organs. The second goal is to use the ex vivo preparation to determine the comprehensive phenotype (CP) of individual visceral sensory neurons. The CP includes an anatomical description of central and peripheral processes, neurochemical characterization, and analysis of action potential shape, conduction velocity and response properties (e.g. threshold, adequate stimulus typing). This information is crucial for the third goal, which is to determine how different populations of visceral afferents (identified on the basis of the CP) respond to insult. For the fourth aim we will repeat these studies in mice lacking the transient receptor potential vaniiloid subfamily receptor 1 (TRPV1, previously known as VR1) to determine if, similar to somatic afferents, this channel is required for development of hypersensitivity.