The effects of opiates on ion transport across the intestinal epithelium will be further investigated. We shall a) examine the ability of opiates from different subclasses to reverse the secretory effects of a variety of agents in different parts of the intestine in vivo; b) examine the contribution of the central nervous system in mediating these intestinal effects of opiates; c) examine the local antisecretory actions of opiates in the guinea-pig ileum. This latter investigation will require a combination of neurophysiological and immunohistochemical techniques. Secondly, we shall investigate further the mechanisms by which kinins stimulate intestinal secretion. In particular, we shall investigate the icosanoid forming potential of the mucosa, the interactions between icosanoids and kinins and the regulation of intracellular enterocyte free calcium by these agents. This latter study will involve the use of the fluorescent dye quin-2. A third investigation will focus on the ability of muscarinic agonists to stimulate ion transport in the intestine. We shall try and elucidate the mechanism of agonist action and in particular the role of calcium in mediating agonist induced ion transport and receptor auto-desensitization. Finally, we shall further investigate the endocrine aspects of the mucosa by investigating the control of 5-HT synthesis and metabolism by mucosal enterochromaffin cells. These studies will help us to further understand the physiology of the intestinal mucosa and its regulation by opiate drugs and other factors. In addition, the studies will also increase our understanding of the molecular mechanisms underlying the action of these same agents.
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