Between 10 and 20 percent of the US population suffers from diseases of the extrahepatic biliary system. This system, which includes the gallbladder, the biliary ducts, and the sphincter of Oddi (SO), must work as a unit to store and concentrate bile between meals, and deliver bile to the lumen of the duodenum following meals. Little is known about the role of nerves in the control of motility in this system, especially with regard to the SO. The SO is a smooth muscle sphincter that surrounds the opening of the common bile duct as it passes through the wall of the duodenum. This sphincter has several functions, including regulation of the flow of bile and pancreatic juices into the gut, and preventing the regurgitation of intestinal contents into the bile or pancreatic ducts. The function of the SO is influenced by extrinsic and intrinsic nerves, as well as by hormones. Within the wall of the sphincter, there exists a plexus of, nerves that comprises clusters of nerve cells, or ganglia. This ganglionated plexus, which is the target of extrinsic neural inputs, is likely to be a primary regulator of the contractile state of the SO. The properties of this neural plexus, and the mechanisms by which it controls the SO, are largely unknown. However, related studies indicate that hormones that relax the SO actually act, at least in part, on neurons in this plexus, rather than directly on smooth muscle. This indicates that the ganglionated plexus of the gallbladder may be a site where external inputs are received and integrated, and where the final signals that control the motility of the SO are generated. The studies proposed in this grant are designed to elucidate the morphological, neurochemical, and physiological features of the intrinsic neural elements of the SO. Studies of the ultrastructure of SO ganglia and the structure of individual neurons within these ganglia will be done. Also, the neurotransmitters that act on the neurons of the SO, and those that are generated by SO neurons, will be determined immunohistochemically. Retrograde tracing studies will be done to determine the sources of extrinsic neural input to the ganglionated plexus of the SO, and to determine whether the circuitry exists for synaptic interaction between neurons in the SO and those in the wall of the gallbladder. Intracellular recording techniques will be used to determine the electrical properties of SO neurons and the types of synaptic input that they receive. These techniques will also be employed to determine how hormonal and sympathetic inputs effect the neurons of the SO, and therefore, how they might influence the output of SO ganglia. In these studies, CCK and norepinephrine will be applied to SO neurons, and both direct and presynaptic actions of the compounds will be assessed. The studies that are outlined in this proposal represent the most in-depth study ever, of the structure and neurochemistry of the ganglionic plexus of any gastrointestinal sphincter. These are also the first studies undertaken, using intracellular recording techniques, to assess the electrical and synaptic properties of the neurons of a smooth muscle sphincter of the bowel.
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