REFLEX PATHWAYS IN THE CONTROL OF INTESTINAL MOTILITY

小肠和大肠中肠神经元的病理变化是许多运动障碍的基础。这些神经元和其他邻近细胞的一氧化氮(NO)含量的变化可能是许多肠道疾病的原因。不仅要了解肠神经回路是如何在肠道的不同区域硬连线以产生其特有的运动模式，而且还要了解一氧化氮如何调节肠神经回路的输出来控制推进。虽然我们开始了解肠神经元是如何安排来产生环状肌(CM)的协调运动的，但纵行肌(LM)的控制和作用仍存在很大争议。通常认为，肌层和肌层是相互支配的，即一个收缩另一个放松；相反，我们最近的发现表明，这两个肌肉层同步运动，在推进过程中一起收缩和放松。此外，尽管人们普遍认为NO是肠平滑肌的抑制性神经递质，但我们的初步发现表明，它也是肠神经在不同回路中调节蠕动的重要兴奋性和抑制性神经调节剂。我们在分离的豚鼠小肠和大肠节段上的初步观察表明，控制LM的肠神经回路在小肠和大肠的不同区域会有所不同，这些差异可能是由于与功能和腔内容物有关的神经投射模式和神经化学的不同所致。因此，本研究的长期目标是确定在豚鼠的回肠、近端结肠和远端结肠这三个不同功能区域中，调节LM的功能和内源性神经回路，以及一氧化氮在调节肠神经元兴奋性中的作用。我们将使用细胞内微电极和张力记录来确定纵向和环状肌层对径向和纵向拉伸和粘膜刺激以及蠕动过程中上行和下行神经通路激活的基本反应。结合更一般的药理分析，将使用NO合成的拮抗剂和NO供体来确定NO在蠕动中的作用。我们还将使用细胞内微电极来鉴定兴奋性和抑制性纵向肌肉运动神经元(LMMN)的电生理、形态和化学编码；突触输入的类型和药理学以及NO对它们的调节；LMMN是否对拉伸敏感，以及它们是如何被粘膜反射和蠕动激活的。通过分析整个孤立器官水平和单个LMMN水平在小肠和大肠这些不同区域到LM的反射路径，我们将能够制定关于LM在推进中的内在神经控制和NO在调节蠕动中的作用的重要的一般原理。

Pathological changes in enteric neurons in both the small and large intestine underlie many motility disorders. Changes in nitric oxide (NO) contents of these neurons and other neighboring cells are likely to be responsible for a number of gut disorders. It is not only important to understand how enteric neural circuits are hard wired in different regions of the bowel to produce their characteristic patterns of motility but also how NO may regulate the output of enteric circuits to control propulsion. Although we are beginning to understand how enteric neurons are arranged to generate coordinated movements of the circular muscle (CM), the control and role of the longitudinal muscle (LM) is subject to much controversy. It is generally assumed that the LM and CM muscle layers are reciprocally innervated, i.e. when one contracts the other relaxes; in contrast, our recent findings suggest that both muscle layers move synchronously, contracting and relaxing together during propulsion. Also, although NO is generally believed to be an inhibitory neurotransmitter to the gut smooth muscle our preliminary findings suggest that it is also both an essential excitatory and inhibitory neuromodulator of enteric neurons in different circuits regulating peristalsis. Our preliminary observations in isolated segments of guinea-pig small and large intestine suggest that the enteric neural circuitry controlling the LM will vary in different regions of the small and large intestine; these differences probably occur owing to differences in neural projection patterns and neurochemistry which relate to function and luminal content. The long term aim of this study, therefore, is to determine the function and intrinsic neural circuitry regulating the LM, as well as the role of nitric oxide in modulating enteric neuron excitability, in three functionally different regions of isolated intestine: ileum, proximal colon and distal colon of the guinea-pig. We will use intracellular microelectrodes and tension recordings to determine the basic responses of the longitudinal and circular muscle layers to activation of ascending and descending nervous pathways by both radial and longitudinal stretch and mucosal stimulation and during peristalsis. Along with a more general pharmacological analysis, antagonists of NO synthesis and NO donors will be used to determine the role of NO in peristalsis. We will also use intracellular microelectrodes to identify the electrophysiological, morphological, and chemical coding of excitatory and inhibitory longitudinal muscle motor neurons (LMMN); the types and pharmacology of synaptic inputs and their regulation by NO; whether LMMNs are stretch sensitive and how they are activated by mucosal reflexes and during peristalsis. By analyzing the reflex pathways to the LM at the whole isolated organ level and at the individual LMMN level in these different regions of the small and large intestine we will be able to formulate important general principles regarding the intrinsic neural control of the LM in propulsion and the roles of NO in modulating peristalsis.