5-Hydroxytryptamine (5-HT) is an important neurotransmitter in both the central and enteric nervous systems. It has diverse functions in regulating gastrointestinal motility and visceral sensitivity, emotion, appetite, pain and sensory perception, cognition, sexual activity and sleep. These functions are mainly associated with the metabolic kinetics of 5-HT in different tissues. Tryptophan hydroxylase is the rate-limiting enzyme and modulates serotonin synthesis. Vesicular monoamine transporter 1 plays a role in 5-HT storage and release. Degradation of 5-HT is mediated by monoamine oxidase-A. All these factors influence the action of 5-HT in vivo. Functional gastrointestinal disorders (FGIDs) are characterized by a series of symptoms including abdominal pain, diarrhea, constipation, anxiety and depression, in the absence of identifiable structural or biochemical abnormalities. They are frequently accompanied by changed gut motility or visceral sensitivity. An increasing body of research has found FGIDs to be closely associated with 5-HT, and drugs such as citalopram, paroxetine, venlafaxine, alosetron, tegaserod, prucalopride and mosapride have all been developed or discovered from the perspective of the metabolic kinetics of 5-HT. This review discusses the relationship between the metabolic kinetics of 5-HT and research targets in the field of FGIDs and suggests areas of future study that may be useful for understanding these disorders and identification of potential therapeutic targets.
AIMTo establish a rat model of anxiety-like gastric hypersensitivity (GHS) of functional dyspepsia (FD) induced by novel sequential stress.METHODSAnimal pups were divided into two groups from postnatal day 2: controls and the sequential-stress-treated. The sequential-stress-treated group received maternal separation and acute gastric irritation early in life and restraint stress in adulthood; controls were reared undisturbed with their mothers. Rats in both groups were followed to adulthood (8 wk) at which point the anxiety-like behaviors and visceromotor responses to gastric distention (20-100 mmHg) and gastric emptying were tested. Meanwhile, alterations in several anxiety-related brain-stomach modulators including 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), brain-derived neurotrophic factor (BDNF) and nesfatin-1 in the rat hippocampus, plasma and gastric fundus and the 5-HT1A receptor (5-HT1AR) in the hippocampal CA1 subfield and the mucosa of the gastric fundus were examined.RESULTSSequential-stress-treated rats simultaneously demonstrated anxiety-like behaviors and GHS in dose-dependent manner compared with the control group. Although rats in both groups consumed similar amount of solid food, the rate of gastric emptying was lower in the sequential-stress-treated rats than in the control group. Sequential stress significantly decreased the levels of 5-HT (51.91 ± 1.88 vs 104.21 ± 2.88, P < 0.01), GABA (2.38 ± 0.16 vs 5.01 ± 0.13, P < 0.01) and BDNF (304.40 ± 10.16 vs 698.17 ± 27.91, P < 0.01) in the hippocampus but increased the content of nesfatin-1 (1961.38 ± 56.89 vs 1007.50 ± 33.05, P < 0.01) in the same site; significantly decreased the levels of 5-HT (47.82 ± 2.29 vs 89.45 ± 2.61, P < 0.01) and BDNF (257.05 ± 12.89 vs 536.71 ± 20.73, P < 0.01) in the plasma but increased the content of nesfatin-1 in it (1391.75 ± 42.77 vs 737.88 ± 33.15, P < 0.01); significantly decreased the levels of 5-HT (41.15 ± 1.81 vs 89.17 ± 2.31, P < 0.01) and BDNF (226.49 ± 12.10 vs 551.36 ± 16.47, P < 0.01) in the gastric fundus but increased the content of nesfatin-1 in the same site (1534.75 ± 38.52 vs 819.63 ± 38.04, P < 0.01). The expressions of 5-HT1AR in the hippocampal CA1 subfield and the mucosa of the gastric fundus were down-regulated measured by IHC (Optical Density value: Hippocampus 15253.50 ± 760.35 vs 21149.75 ± 834.13; gastric fundus 15865.25 ± 521.24 vs 23865.75 ± 1868.60; P < 0.05, respectively) and WB (0.38 ± 0.01 vs 0.57 ± 0.03, P < 0.01) (n = 8 in each group).CONCLUSIONSequential stress could induce a potential rat model of anxiety-like GHS of FD, which could be used to research the mechanisms of this intractable disease.
Abstract:Objective: To analyze reflux parameters by means of combined multichannel intraluminal impedance and pH (MII-pH) monitoring in patients with gastroesophageal reflux disease (GERD) symptoms off medication, and to find the reflux characteristics of Chinese GERD patients and the influences of gender, age, body posture, and body mass index (BMI) on gastroesophageal reflux (GER). Methods: Between Dec. 2008 and May 2014, 125 patients with typical GERD symptoms were subjected to 24-h MII-pH monitoring. Twelve patients with normal MII-pH profiles were not considered for analysis. The reflux parameters of 113 GERD patients with abnormal MII-pH results were analyzed. Results: (1) DeMeester scores were above the normal range in 46.90% (53/113) of GERD patients. Weakly acidic refluxes were prevalent in GERD patients, and the frequency of abnormal weakly acidic reflux was 75.22% (85/113). The frequencies of abnormal symptom index (SI) and symptom association probability (SAP) were 19.47% (22/113) and 14.16% (16/113), respectively. (2) The frequencies of DeMeester scores, the %time at pH<4, and the numbers of reflux episodes and of long reflux episodes >5 min were significantly higher in male patients than in female patients. (3) The %time at pH<4 was much higher during upright periods than during supine periods. During supine periods, 31.86% (36/113) of GERD patients had delayed bolus clearance time, compared with 19.47% (22/113) during upright periods. (4) The number of abnormal DeMeester scores, %time at pH<4, and the number of acid refluxes during upright periods were significantly higher in obese GERD patients than in GERD patients with a normal BMI. Overweight GERD patients also had many more acid refluxes during upright periods than GERD patients with a normal BMI. Conclusions: Weakly acidic refluxes were prevalent in Chinese GERD patients. The factors male, gender, upright position, obesity (BMI≥25), but not age, may increase the frequency and severity of GER.
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