Activation of Nociceptors in Esophagus

描述（申请人提供）：食道内的感觉神经对食道生理功能的调节至关重要。感觉神经也调节意识感觉（烧心、疼痛）和食道的防御反射。食道感觉神经功能异常可导致与组织损伤不成比例的疼痛和功能障碍。在许多情况下，食道感觉神经激活的后果带来了诊断和治疗难题，如起源于食道的功能性烧心或非心源性胸痛（NCCP）。尽管它们很重要，但对食道感觉的分子机制仍然知之甚少。当涉及到食道传入疼痛纤维（痛觉感受器）的基本生物学时，这一领域的进展尤其有限。因此，本研究主要围绕食道痛觉神经及其激活的分子机制展开。在Aim 1中，我们提出了我们的新假设，即基于胚胎起源，食道中至少有两种不同的伤害神经亚型。这些亚型在激活谱和神经递质化学上都有所不同。在目标2和目标3中，我们提出了与食道感觉的某些关键介质，酸和腺苷，在食道伤害感受器的神经末梢唤起动作电位放电的机制有关的假设。食道中的酸会引发不同的感觉，包括胃灼热和疼痛。腺苷最近被认为与非心源性胸痛有关。在目标2中，我们将结合分子生物学和电生理学技术来评估我们的假设，即除了辣椒素敏感的TRPV1受体外，酸还通过某些酸感离子通道（ASIC）激活食道伤害感受器。在目的3中，我们将研究参与腺苷受体介导的食管伤害感觉末梢动作电位放电的离子通道的性质。我们假设g蛋白连接的腺苷受体通过信号转导方案介导食道伤害感受器的激活，从而打开某些氯离子通道和TRPV1。我们将在野生型小鼠和具有战略性基因突变的小鼠中使用解剖学和各种电生理技术的组合来解决我们的假设。

DESCRIPTION (provided by applicant): Sensory nerves in the esophagus are essential for the regulation of its physiological function. Sensory nerves also mediate conscious sensations (heartburn, pain) and defensive reflexes from the esophagus. Perverted function of esophageal sensory nerves may result in pain and dysfunction disproportionate to the tissue injury. In many instances, the consequences of the esophageal sensory nerve activation present diagnostic and therapeutic dilemmas such as functional heartburn or non-cardiac chest pain (NCCP) originating in the esophagus. Despite their importance, the molecular mechanisms underlying esophageal sensations remain poorly understood. Progress in this area has been especially limited when it comes to the basic biology of the afferent pain fibers (nociceptors) in the esophagus. Accordingly, this proposal centers specifically on esophageal nociceptive nerves and the molecular mechanisms of their activation. In Aim 1 we address our novel hypothesis that, based on embryonic origin, there are at least two distinct nociceptive nerve subtypes in the esophagus. These subtypes differ in both activation profile and neurotransmitter chemistry. In Aim 2 and Aim 3 we address hypotheses relating to the mechanisms by which certain key mediators of esophageal sensations, acid and adenosine, evoke action potential discharge in the nerve terminals of esophageal nociceptors. Acid in the esophagus initiates disparate sensations including heartburn and pain. Adenosine has been recently implicated in non-cardiac chest pain. In aim 2 we will combine molecular biological and electrophysiological techniques to evaluate our hypothesis that acid activates esophageal nociceptors via certain acid sensing ion channels (ASIC) in addition to the capsaicin-sensitive TRPV1 receptor. In aim 3 we will investigate the nature of ion channels involved in adenosine receptor-mediated action potential discharge in esophageal nociceptive terminals. We hypothesize that the G-protein linked adenosine receptors mediate activation of esophageal nociceptors by a signal transduction scheme that results in opening certain chloride channels and TRPV1. We will address our hypotheses using a combination of anatomical and various electrophysiological techniques in wild type mice and mice with strategic genetic mutations.