PYY AND NPY - CONTROL OF GASTRIC-MOTILITY VIA ACTION ON Y1 AND Y2 RECEPTORS IN THE DVC

The pancreatic polypeptide family of hormones and neurotransmitters in cluding pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY) are emerging as potent central regulators of gastric function . There is, however, considerable debate concerning the mechanisms and even the direction of effects mediated by these peptides. Good eviden ce exists showing that PYY is the 'enterogastrone' released by the ile um after feeding which acts on vagal reflex control circuits to reduce gastric motility (i.e. the 'ileal brake'). However, equally convincin g evidence is available to suggest that PW and its close structural re lative NPY may act in the same region of the brain to increase gastric motility through vagal mechanisms. We hypothesize that the confoundin g observations are due to agonist effects on two different receptor ty pes - Y1 and Y2, which are both present in the dorsal vagal complex (D VC) but may be accessed differentially by peripheral humoral (PYY) vs central (NPY) pathways. In our initial approach to this problem, we st udied the effects of NPY, PM: YZ and Y2 agonists microinjected into th e DVC on gastric motility in the stimulated (by central thyrotropin-re leasing hormone (TRH)) and basal conditions. Our results show that Y2 agonist applied to the DVC during conditions of TRH-stimulated gastric motility mimicked the suppressive effects of PYY applied under the sa me conditions. Under basal conditions, Y2 agonist has no effect on mot ility. The DVC effect of the Y1 agonist is the opposite; Y1 agonist ha s no further effect to stimulate gastric motility in the TRH stimulate d condition while Y1 agonist strongly stimulates motility from the bas al condition. The effects of NPY depend upon the condition of study. U nder TRH stimulation (maximal motility), NPY in DVC reduces (but does not completely suppress) gastric motility while in the basal state, NP Y is a strong activator of motility. These results are discussed in te rms of the possible differential localization of Y1 vs Y2 receptors wi thin the DVC and in terms of recent findings suggesting that PYY is ra pidly converted to a Y2 agonist by a ubiquitous dipeptidyl aminopeptid ase (DAP-IV).