Gastric dysreflexia after spinal cord injury

描述（由申请人提供）：脊髓损伤（SCI）最明显的后果是感觉和运动功能的立即丧失。然而，在绝大多数患者中发生胃肠道（GI）功能的显著损害，其中许多患者具有需要肠内喂养的严重抑制的胃动力。这些疾病的病理生理学仍不完全清楚，但在以前的资助期间收集的数据指向迷走神经传入信号从胃肠道到延髓孤束核（NTS）的反应性降低。例如，SCI导致1）胆囊收缩素（CCK）的餐后血清表达减少; 2）外周硫酸化CCK（CCK-8）后NTS激活减少; 3）将CCK-8中央显微注射到NTS后胃抑制减少;和4）CCK-8浴应用后兴奋性突触后电流的体外全细胞记录减少。NTS神经元的一个亚类向迷走神经背侧运动核（DMV）的运动神经元提供紧张性抑制（GABA）输入，DMV构成迷走-迷走GI反射的迷走运动肢。 我们的新的试点数据已经确定了类似的紊乱的促动力GI肽，胃饥饿素。我们假设脊髓损伤后肠-脑轴内传入信号的减少可能使NTS-DMV活性偏向于抑制性GABA能静息张力。这种非对抗性抑制信号可能是SCI后导致GI运动障碍的一种机制。虽然对生长素释放肽的治疗潜力的临床兴趣正在出现，但生长素释放肽模拟物用于SCI患者的治疗功效可能会降低。 在本建议中，我们将使用T3-SCI的动物模型结合体内生理（胃排空或运动和迷走神经）记录，和分子（RT-PCR和ELISA）的方法，目的是定义导致SCI后GI功能丧失的机制。我们的总体假设是脊髓损伤减少迷走神经传入信号，并通过脑干迷走神经回路中不受调节的GABA能信号引起胃动力障碍。 具体来说，我们将检验以下假设：1）胃脑干回路的迷走传入信号减少是由GI肽释放减少介导的; 2）胃脑干回路内突触前神经元能信号减少是由迷走传入神经对GI肽的敏感性降低介导的; 3）降低迷走神经传入和NTS神经元对进食的敏感性-相关肽使GI脑干回路偏向于对DMV传出流出到胃的紧张性GABA能抑制。本提案产生的数据将提供新的信息的疗效的治疗策略，以减少GI动力障碍SCI后，从而改善消化过程的功能结果。这项建议将提供基础，以完善一个模型的SCI后改变胃肠道功能，包括整个长度的胃肠道。最终，这将有助于缓解SCI患者的GI功能障碍。

DESCRIPTION (provided by applicant): The most apparent consequence of spinal cord injury (SCI) is the immediate loss of sensation and motor function. However, a dramatic impairment of the functionality of the gastrointestinal (GI) tract occurs in the vast majority of the patients, many of whom have a severely depressed gastric motility that necessitates enteral feeding. The pathophysiology of these disorders remains incompletely understood, but data gathered during the previous funding period point toward diminished responsiveness of vagal afferent signaling from the GI tract to the nucleus tractus solitarius (NTS) in the medulla. For example, SCI results in 1) diminished postprandial serum expression of cholecystokinin (CCK); 2) diminished NTS activation following peripheral sulfated CCK (CCK-8s); 3) diminished gastroinhibition following central microinjection of CCK-8s into the NTS; and 4) diminished in vitro, whole cell recordings of excitatory post-synaptic currents following bath application of CCK-8s. A subclass of NTS neurons provide a tonic inhibitory (GABA) input onto motoneurones of the dorsal motor nucleus of the vagus (DMV), which composes the vagal motor limb of vago-vagal GI reflexes. Our novel pilot data have identified similar derangements to the prokinetic GI peptide, ghrelin. We hypothesize that a post-SCI reduction in afferent signaling within the gut-brain axis may bias NTS-DMV activity in favor of an inhibitory GABAergic resting tone. This unopposed inhibitory signal may be one mechanism leading to GI dysmotility following SCI. While clinical interest in the therapeutic potential of ghrelin is emerging, the therapeutic efficacy of ghrelin mimetics may be diminished for use in SCI patients. In the present proposal we will use an animal model of T3-SCI combined with in vivo physiological (gastric emptying or motility and vagus nerve) recording, and molecular (RT-PCR and ELISA) approaches with the aim of defining the mechanisms resulting in the loss of GI function after SCI. Our overarching hypothesis is that spinal cord injury reduces vagal afferent signaling and provokes gastric dysmotility through unregulated GABAergic signaling within brainstem vagal circuits. Specifically we will test the hypotheses that 1) reduced vagal afferent signaling to gastric brainstem circuits is mediated by diminished GI peptide release; 2) reduced presynaptic glutamatergic signaling within gastric brainstem circuits is mediated by reduced sensitivity of vagal afferents to GI peptides; 3) reduced vagal afferent and NTS neuronal sensitivity to feeding-related peptides biases GI brainstem circuits toward a tonic GABAergic inhibition of DMV efferent outflow to the stomach. The data generated by the present proposal will provide novel information regarding the efficacy of therapeutic strategies to reduce GI dysmotility following SCI, thereby improving functional outcome of digestive processes. This proposal will provide the basis to refine a model of post-SCI alterations in gastrointestinal function that encompasses the entire length of the GI tract. Ultimately this will help alleviate GI dysfunctions in SCI patients.