Characterization and Plasticity of Visceral Nociceptors

描述（由申请方提供）：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，可在无任何明显结构异常的情况下发生（例如肠易激综合征）。内脏疼痛还显著地导致许多慢性疾病的衰弱性质（例如与克罗恩病相关的疼痛）。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疾病的治疗方法。最近，在理解躯体疼痛方面取得了重大进展。在很大程度上，这是由于分子和遗传模型的发展，允许更高水平的分辨率比以前可能的。众所周知，内脏传入与躯体传入非常不同[26]。然而，如果用于检查躯体伤害感受的技术可以适用于内脏感觉系统，同样重要的进展，可以阐明内脏疼痛的基本机制。为此，本实验结合联合收割机的行为，解剖，生理和遗传的方法来研究小鼠的内脏传入。将使用一种新的“离体”生理学范例，其保留了整个感觉神经元，包括其与器官（在这种情况下为结肠）的外周连接和其与脊髓的中枢连接。该应用程序有4个具体目标：第一个是确定投射到不同腹部和盆腔器官的内脏传入的异质性。第二个目标是使用离体制备来确定个体内脏感觉神经元的综合表型（CP）。CP包括中枢和外周过程的解剖学描述、神经化学表征以及动作电位形状、传导速度和响应特性（例如阈值、适当刺激类型）的分析。这一信息对于第三个目标至关重要，即确定不同的内脏传入（根据CP识别）群体如何对侮辱做出反应。对于第四个目标，我们将在缺乏瞬时受体电位香草酸亚家族受体1（TRPV1，以前称为VR1）的小鼠中重复这些研究，以确定是否与躯体传入相似，该通道是超敏反应发展所必需的。

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.