NEURAL CONTROL OF LARGE INTESTINAL MUCOSA

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Diarrhea is one of the symptoms associated with food allergies, parasitic infections and inflammatory bowel disease. Histamine from mast cells is one of multiple mediators implicated in the pathogenesis of these diseases. The overall goal is to examine the mechanisms by which histamine mediates coordinated secretory and contractile behavior in the colon of guinea pigs. The first aim addresses the efferent pathways in the submucous plexus that mediate histamine-evoked cyclical secretion in normal animals. Submucosa/mucosa preparations will be set up in flux chambers for recording short-circuit current which reflects ion transport. Studies will identify the types of submucous neurons that have histamine H2 receptors, test whether H3 receptors modulate neurotransmitter release, and determine whether cholinergic or VIP secretomotor neurons are necessary to induce cyclical secretion. Neural pathways will be identified by pharmacological analysis, release of 3H- acetylcholine and VIP, intracellular electrophysiologic recording and injection techniques and immunohistochemical staining methods. The second aim is to determine if extrinsic or intrinsic neural reflex pathways coordinate cyclical secretory and contractile behavior to histamine in normal animals. For these studies whole thickness segments will be set up in flux chambers. Muscle tension, recorded from a strain gauge transducer sutured to the serosal surface, will be determined simultaneously with ion transport. These studies will show whether cyclical contraction is dependent on the rate of cyclical secretion, whether intact neural pathways between the submucosa/mucosa and muscle are necessary for coordination of function and whether these pathways are of intrinsic or extrinsic origin. Neural reflex pathways coordinating cyclical secretion and muscle contraction will be assessed by chemical ablation with capsaicin, surgical ablation of extrinsic neural pathways and pharmacological antagonism. The third aim is to determine whether endogenous histamine from mast cells evokes coordinated cyclical secretion and contraction in guinea pigs sensitized to the bovine milk antigen, beta-lactoglobulin. These studies are expected to provide important insights into neuro-immune signals that result in altered secretory states associated with inflammatory diseases.