This project will carry out in parallel pharmacological studies to characterize receptor-selective CCK-related peptide actions on gastrointestinal transit in mice and on regional transit in rats, analgesia, food ingestion, and on gastrointestinal motility, and patterns of motility in vivo associated with a stress response and identification of central and peripheral mediators of the response. In our peptide design and synthesis program supported by this grant, we have developed some extraordinarily promising lead compounds that we will refine chemically to generate highly selective agonists at CCKA and CCKB receptors. In combination with existing nonpeptide antagonists, such as L-364,718 and L- 365,260, plus natural and synthetic analogues of CCK, we will define the motility responses, transit consequences and appetite regulating activity of brain and peripheral CCKA, CCKB and gastrin receptor. Moreover, our preliminary studies provide strong evidence for multiple subtypes of CCKB receptors in the brain and in the periphery. Different CCKB subtypes in brain may be linked to inhibition of food ingestion and g.i. antitransit effects. A subtype of CCKB receptor may be associated with peripheral antiappetite effects of CCK. The in vitro and in vivo models to be employed are familiar techniques in our laboratory. Specifically, we will measure motility in unanesthetized rats of the stomach, small intestine, cecum and colon and correlate motility changes with alterations in transit (propulsion) in each of these regions after central (i.c.v.) and peripheral (i.v.) administration of receptor-selective peptide agonists. We will also assess effects of the peptides on consumption of a highly palatable meal to establish whether CCKA and CCKB receptors mediate satiety effects. Finally, we will characterize specific changes in regional gastrointestinal motility associated with an established model of stress and determine how CRF, opioids, catecholamines, or CCK may be involved in stress-induced motility patterns.
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