There are a large number of transmitters and receptors contained in enteric nerves. The interaction of nerves, and the substances they release, with other nerves and with intestinal smooth muscle is poorly understood. The principal aims of this proposal are to determine some of the specific neural connections in the myenteric plexus which coordinate propulsive contractions in the small intestine. This will be accomplished in 3 projects. The first project will use intracellular electrophysiological techniques to study drug receptors on neuronal cell bodies by measuring changes in membrane potential following drug application, and on nerve terminals by measuring drug-induced changes in synaptic potentials. Preliminary data indicate that groups of drug receptors may be co-localized on the soma and nerve terminals of specific subsets of neurons and receptor neurons. These studies will focus on opioid, 5-HT, and alpha2 adrenergic receptors. The electrophysiologically and pharmacologically identified neurons will be marked with an intracellular dye and the tissues processed for immunohistochemical localization of the neuropeptides substance P and vasoactive intestinal peptide in neurons. The second project will use pharmacological and microsurgical techniques to determine the transmitters and pathways involved in the peristaltic reflex. The third project will use intracellular electrophysiological techniques to record from myenteric neurons during peristalsis. The results of these three projects would describe, in detail, the neural circuitry underlying reflex contractions of the small intestine. Specific functions would be assigned to identified neurons and the actions of drugs could be attributed to an effect on specific neurons. These data would have applications to basic neurobiology in describing the functions of a complete nerve network. Additional benefits could be derived from the development of therapies for disorders of gastrointestinal motility involving enteric nerves. These disorders include Hirshprung's disease, colitis and ileitis, the irritable bowel syndrome and neuropathies associated with diabetes.
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