Our objective is to understand the role of the enteric nervous system, which consists of the myenteric and submucosal plexuses, in the control of intestinal motility and mucosal transport. It has been difficult to define the regulatory function of these plexuses because they are found within the gut wall and therefore are not directly accessible to physical dissection. Our approach to this problem is to ablate a component of the enteric nervous system in order to define the function of the ablated component. We have selectively destroyed myenteric neurons by the application of chemicals with surfactant properties to the serosa of the rat jejunum. As a result of this surfactant treatment, myenteric neuronal function is lost as indicated by the lack of response to ganglionic-stimulating drugs. In contrast to the loss of neuronal function, the smooth muscle of both surfactant-treated and normal jejunum contracts equally to muscarinic receptor agonists. By extending this use of surfactants, we plan to obtain 2 other models: submucosal-denervated and totally denervated gut. We will examine in vivo and in vitro denervated preparations for alterations in motility and mucosal transport by studying the responses to electrical stimulation and to drugs and peptides acting on enterocytes, nerve, or muscle. Furthermore, after denervation, we will quantitate changes in endogenous mediators to determine their distribution in order to correlate distribution with function. We will also evaluate the possibility that the basic electrical rhythm of the intestine is produced by the interstitial cells of Cajal and is modulated by enteric neurons. The use of surfactants to ablate neurons selectively is unique. This approach will clarify the role of the enteric nerves in normal gut function and serve as a model for congenital and acquired pathology, i.e., Hirschsprung and Chagas diseases, and may explain why several pharmacological agents alter gastrointestinal activity. Our recent studies indicate that we are approaching our objectives. We have been successful in obtaining a chronic, totally denervated gut segment by combining anoxia with benzalkonium chloride treatment. In addition, we have demonstrated that clinically used drugs such as quinacrine or chlorpromazine can also ablate myenteric neurons following serosal application in a dose-dependent manner similar to the surfactants.
