Characterization and Plasticity of Visceral Nociceptors

内脏伤害感受器的特征和可塑性

• 批准号: 7008212
• 负责人: BRIAN M DAVIS
• 金额: $ 32.82万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008212
• 关键词: action potentials; biotin; cholera toxin; colon; enteric nervous system; histochemistry /cytochemistry; laboratory mouse; membrane channels; nerve injury; neural conduction; neural plasticity; neuroanatomy; neurochemistry; nociceptors; pain; phenotype; sensory thresholds; spinal ganglion; stomach; urinary bladder; visceral afferent nerve

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.

描述（由申请人提供）：内脏感觉神经元引起的病理疼痛是器官功能障碍不可或缺的，并且可以在没有任何明显的结构异常（例如肠易激综合征）的情况下发生。内脏疼痛也对许多慢性疾病（例如与克罗恩斯氏病有关的疼痛）的使人衰弱的性质显着贡献。内脏感官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疗法。最近，在低估体细胞疼痛方面已取得了重大进展。在很大程度上，这是由于分子和遗传模型的发展，这些模型允许比以前可能更高的分辨率。众所周知，内脏传入与躯体传入量大不相同[26]。但是，如果可以针对内脏的感觉系统进行调整用于检查体细胞伤害感的技术，则可以做出同样重要的进展，以阐明内脏疼痛的基本机制。为此，目前的实验结合了研究小鼠内脏传入的行为，解剖学，生理和遗传方法。将使用一种新颖的“ Ex Vivo”生理范式，该范式保留了整个感觉神经元，包括其与器官的周围连接（在这种情况下为结肠）及其与脊髓的中心连接。该应用程序具有4个特定目标：首先是确定投射到不同腹部和骨盆器官的内脏传入的异质性。第二个目标是使用离体准备工作来确定个体内脏感觉神经元的综合表型（CP）。 CP包括对中央和周围过程的解剖描述，神经化学表征以及分析动作势形状，传导速度和响应特性（例如阈值，适当的刺激键入）。该信息对于第三个目标至关重要，即确定不同的内脏传入人群（根据CP确定）如何应对侮辱。对于第四个目标，我们将在缺乏瞬态受体潜在的Vaniiloid亚家族受体1（TRPV1，以前称为VR1）的小鼠中重复这些研究，以确定是否类似于体细胞传入，此通道是否需要发展高敏性。