The objectives of the present research proposal are to investigate: 1) details of the nonadrenergic-noncholinergic inhibitory neurotransmission in the IAS; 2) the neural pathways and role of regulatory neurohumoral substances such as opiates in basal IAS tone and rectoanal inhibitory reflex-induced IAS relaxation; and 3) the cellular basis of the intrinsic myogenic tone in the IAS, particularly the so-called latch state. Studies are planned in vivo and in vitro in which the activity of the IAS will be isolated from that of the external anal sphincter (EAS) by simultaneous electrical and mechanical recordings. Studies will be performed to examine the structure-activity relationship, receptor binding, second messengers, immunocytochemical localization of physiologically relevant neuropeptides, radioimmunoassay (RIA) of neuropeptides, the direct release of mediators, membrane potential changes using intracellular electrical recordings, changes in the free intracellular Ca2+, PI turnover, protein kinase C and myosin light chain phosphorylation. While these studies will yield a diverse spectrum of information, they will be specifically aimed at elucidating specific objectives. These studies will be performed in opossums, but other animal species will also be used to determine species differences in the control of the sphincter. The proposed studies should provide important information leading to a better understanding of the pathophysiology and the treatment of anorectal disorders.
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