REFLEX PATHWAYS IN THE CONTROL OF INTESTINAL MOTILITY

小肠和大肠中肠神经元的病理改变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）含量的变化可能是导致许多肠道疾病的原因。了解肠神经回路如何在肠的不同区域硬连接以产生其特有的运动模式，以及NO如何调节肠回路的输出以控制推进，这不仅很重要。虽然我们开始了解肠神经元是如何安排以产生环形肌（CM）的协调运动的，但纵肌（LM）的控制和作用受到许多争议。一般认为LM肌层和CM肌层是相互神经支配的，即当一个收缩时另一个松弛；相反，我们最近的研究结果表明，这两个肌肉层是同步运动的，在推进过程中收缩和放松在一起。此外，虽然一氧化氮通常被认为是肠道平滑肌的抑制性神经递质，但我们的初步研究结果表明，它也是调节肠蠕动不同回路中肠神经元必不可少的兴奋性和抑制性神经调节剂。我们对豚鼠小肠和大肠分离段的初步观察表明，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管腔含量有关的神经投射模式和神经化学的差异造成的。因此，本研究的长期目标是确定豚鼠离体肠三个功能不同区域：回肠、近端结肠和远端结肠中调节LM的功能和内在神经回路，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圆形肌肉层对通过径向和纵向拉伸以及粘膜刺激和蠕动激活上行和下行神经通路的基本反应。与更一般的药理学分析一起，NO合成拮抗剂和NO供体将被用来确定NO在蠕动中的作用。我们还将使用细胞内微电极来识别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、药理作用及其受NO的调控；lmmn是否拉伸敏感，以及它们是如何被粘膜反射和蠕动激活的。通过分析小肠和大肠不同区域的整个孤立器官水平和单个LMMN水平上的LM反射通路，我们将能够制定关于LM推进的内在神经控制和NO在调节蠕动中的作用的重要一般原则。

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.