Slowing intestinal transit by PYY depends on serotonergic and opioid pathways

Slowing of intestinal transit by fat is abolished by immunoneutralization of peptide YY (PYY), demonstrating a key role for this gut peptide. How PYY slows intestinal transit is not known. We tested the hypothesis that the slowing of intestinal transit by PYY may depend on an ondansetron-sensitive serotonergic pathway and a naloxone-sensitive opioid pathway. In a fistulated dog model, occluding Foley catheters were used to compartmentalize the small intestine into proximal (between fistulas) and distal (beyond midgut fistula) half of gut. Buffer (pH 7.0) was perfused into both proximal and distal gut, and PYY was delivered intravenously. Ondansetron or naloxone was mixed with buffer and delivered into either the proximal or distal half of gut. Intestinal transit was measured across the proximal half of the gut. The slowing of intestinal transit by PYY was abolished when either ondansetron or naloxone was delivered into the proximal, but not the distal gut, to localize the two pathways to the efferent limb of the slowing response. In addition, 5-HT slows intestinal transit with marker recovery decreased from 76.2 +/- 3.6% (control) to 33.5 +/- 2.4% (5-HT) (P < 0.0001) but was reversed by naloxone delivered into the proximal gut with marker recovery increased to 79.9 +/- 7.2% (P < 0.0005). We conclude that the slowing of intestinal transit by PYY depends on serotonergic neurotransmission via an opioid pathway.