PMC

Dopamine is depleted in the intestines but not in the brains of mice lacking TPH2. Levels are shown for TPH1/2dKO animals and their wild-type littermates; however, the level of dopamine in the gut of TPH1KO mice is not significantly different from that of wild-type animals. The levels of dopamine in the bowel of TPH2KO mice are not significantly different from those of the TPH1/2dKO mice that are shown.

TPH2 immunoreactivity (red) is present in neurons of the myenteric plexus of the mouse intestine. Antibodies to HuC/D (blue) are used as a neuronal marker and reveal the cell bodies of all neurons. Double label immunoreactivity demonstrates both antigens in the same sections. Left panel: TPH2 immunoreactivity. Center panel: HuC/D immunoreactivity. Right panel: Merged image. Note that TPH2 is found in 2 neurons (arrows) but not in all and that it also extends into varicose axons running in interganglionic connectives (arrowheads). The marker = 25 μm.

A cartoon showing the layers of the bowel wall and the cells thought to be active in mediating the peristaltic reflex. Increased intraluminal pressure initiates the secretion of 5-HT from EC cells in the epithelium of the intestinal mucosa. 5-HT stimulates the mucosal projections of intrinsic primary afferent neurons (IPANs). Although these cells are found in both the submucosal and myenteric plexuses, only a submucosal IPAN is shown. IPANs activate ascending and descending interneurons, which in turn stimulate orad excitatory and distal inhibitory motor neurons, respectively. The interneurons enable the peristaltic reflex to manifest ascending excitation and descending inhibition of smooth muscle. Excitatory motor neurons use acetylcholine (ACh) and/or a tachykin to trigger contraction of the circular muscle, whereas inhibitory motorneurons use NO and/or a purine (β-NAD or ATP) to evoke muscle relaxation. Most interneurons are cholinergic and activate nicotinic receptors; however, 5-HT is also a transmitter of descending myenteric interneurons.

Total GI transit time, small intestine transit, and colonic motility are decreased in TPH2KO and TPH1/2dKO mice; however, gastric emptying is accelerated in the same animals. (A) Carmine red was administered orally and transit time was considered as the time required for the red color to appear in feces. GI transit time in TPH1KO, TPH2KO, and TPH1/2dKO mice was compared, respectively, to that of the wild-type littermates of each of these types of mouse. Total GI transit time was increased (slower than littermates) in TPH2KO and TPH1/2dKO animals but not in TPH1KO mice. Total GI transit time in TPH1/2dKO animals was not significantly different from that in TPH2KO mice. (B) Gastric emptying was measured after rhodamine dextran gavage. The proportion of gavaged rhodamine dextran emptying from the stomach in 15 minutes was compared in TPH1KO, TPH2KO, and TPH1/2dKO mice and their respective wild-type littermates. Gastric contents emptied to a greater extent in TPH2KO and TPH1/2dKO, but not in TPH1KO, animals than in their littermates. Gastric emptying in TPH1/2dKO animals was not significantly different from that in TPH2KO mice. (C) Small intestinal transit was evaluated as the geometric center of rhodamine dextran in the small bowel. Geometric centers of 1 to 10 represent slow to fast small intestine transit. Small intestinal transit was significantly slower in TPH2KO and TPH1/2dKO but not in TPH1KO animals than in their respective wild-type littermates. Small intestinal transit in TPH1/2dKO animals was not significantly different from that in TPH2KO mice. D. Colonic motility was estimated as the time for expulsion of a glass bead pushed into the rectum a distance of 2 cm from the anal verge. This time was significantly greater (slower motility) in TPH2KO and TPH1/2dKO but not in TPH1KO animals than in their respective wild-type littermates. Expulsion time in TPH1/2dKO mice was not significantly different from that in TPH2KO mice. (ns = not significant.) (From Li et al. [3].)