-Sheng Li

The role of the vagal pathway and gastric dopamine in the gastroparesis of rats after a 6‐hydroxydopamine microinjection in the substantia nigra

Gastroparesis is a common non‐motor system symptom of Parkinsons disease (PD). However, the mechanism responsible for the gastric motor abnormality is not clear. We previously reported on the impaired gastric motility in 6‐hydroxydopamine (6‐OHDA) rats, which were treated with a bilateral microinjection of 6‐OHDA in the substantia nigra (SN). We hypothesize that the enhanced dopamine system and reduced acetylcholine (Ach) in gastric tissues might contribute to the delayed gastric emptying observed in PD.

Dopamine receptor D1 mediates the inhibition of dopamine on the distal colonic motility

The motility of distal colon could be inhibited by dopamine (DA), yet, the involved receptor is controversial according to the published reports. The goal of present study was to investigate DA receptor(s) mediated inhibition of DA on the colonic motility in rat. The contraction of isolated colon strips was assessed through isometric force transducer. The expressions of DA receptors in distal colon were detected through immunofluorescence and Western blot. DA concentration in colonic smooth muscle was measured by liquid chromatography/mass spectrometry. The results showed that DA inhibited the spontaneous motility of distal colon in a dose-dependent manner with EC50 8.3 μM. Tetrodotoxin increased colonic contractive frequency, but failed to affect the inhibition of DA on the colonic motility. Pretreatment with SCH-23390, an antagonist of dopaminergic receptor D1, shifted the dose-response curve to the right with EC50 of DA 37 μM. However, blocking dopaminergic receptor D2 with sulpiride, had no effect. The immunoreactivity of D1 and D2 were detected in the distal colon including myenteric plexus and smooth muscle. Acute cold-restraint stress (CRS) enhanced spontaneous contraction of rat distal colon, which was more sensitive to DA compared with control. Moreover, DA content and D1 expression in smooth muscle layer were increased under CRS condition. In conclusion, D1 in the smooth muscle is mediated DA inhibition on the spontaneous contraction of rat distal colon. The increased DA content and D1 receptor expression in the smooth muscle layer could be a compensatory effect under CRS condition to balance the enhanced colonic motility.

Alteration of enteric monoamines with monoamine receptors and colonic dysmotility in 6-hydroxydopamine-induced Parkinson's disease rats.

Constipation is common in Parkinsons disease (PD), in which monoamines (dopamine [DA], norepinephrine [NE], and 5-hydroxytryptamine [5-HT]) play an important role. Rats microinjected with 6-hydroxydopamine (6-OHDA) into the bilateral substantia nigra (SN) exhibit constipation, but the role of monoamines and their receptors is not clear. In the present study, colonic motility, monoamine content, and the expression of monoamine receptors were examined using strain gauge force transducers, ultraperformance liquid chromatography tandem mass spectrometry, immunofluorescence, and Western blot. The 6-OHDA rats displayed a significant reduction in dopaminergic neurons in the SN and a decreased time on rota-rod test and a marked decrease in daily fecal production and fecal water content. The amplitude of colonic spontaneous contraction was obviously decreased in 6-OHDA rats. Blocking D1-like receptor and β3-adrenoceptor (β3-AR) significantly reduced the inhibition of DA and NE on the colonic motility, respectively, whereas the 5-HT and 5-HT4 receptor agonists promoted the colonic motility. Moreover, DA content was increased in the colonic muscularis externa of 6-OHDA rats. The protein expression of β3-ARs was notably upregulated, but 5-HT4 receptors were significantly decreased in the colonic muscularis externa of 6-OHDA rats. We conclude that enhanced DA and β3-ARs and decreased 5-HT4 receptors may be contributed to the colonic dysmotility and constipation observed in 6-OHDA rats.

Emodin induces chloride secretion in rat distal colon through activation of mast cells and enteric neurons

BACKGROUND AND PURPOSE Emodin (1,3,8‐trihydroxy‐6‐methylanthraquinone) is an active component of many herb‐based laxatives. However, its mechanism of action is unclear. The aim of the present study was to investigate the role of mast cells and enteric neurons in emodin‐induced ion secretion in the rat colon.

Entacapone promotes cAMP-dependent colonic Cl(-) secretion in rats.

Background  Entacapone is a promising drug used widely for the treatment of Parkinson’s disease (PD) as a catechol‐O‐methyl transferase (COMT) inhibitor. However, entacapone has gastrointestinal side effects. The aim of this study was to investigate the effects of entacapone on the epithelial ion transport in rat distal colon, and explore the underlying mechanism.

Colonic submucosal 5-HT3 receptor-mediated somatostatin-dependent secretoinhibitory pathway is suppressed in water-immersion restraint stressed rats

We have demonstrated that the activation of 5-hydroxytryptamine (5-HT) receptor 3 in the submucosal plexus suppresses 5-HT-induced colonic ion secretion by increasing submucosal somatostatin release. A number of psychological and physical stresses have impacts on the intestinal mucosal functions, including secretion and the epithelial barrier. Whether the 5-HT(3) receptor-mediated somatostatin-dependent secretoinhibitory pathway in the rat distal colon is involved in the stress process is still unknown. The present study aims to investigate the effect of the water-immersion restraint stress on this inhibitory pathway and its underlying mechanisms. Mucosa/submucosa preparations from the rat distal colon were mounted in the Ussing chambers for the measurement of short-circuit current (I(SC)). Real-time PCR and western blot were performed to study the expression of the 5-HT(3) receptor, 5-HT(4) receptor, and somatostatin receptor 2. Radioimmunoassay was used to measure somatostatin release. After 2h of water-immersion restraint stress, the membrane resistance (Rte) of rat mucosa/submucosa preparations was significantly decreased, but the baseline I(SC) and 5-HT-induced I(SC) responses were significantly increased. The protein expression of the submucosal 5-HT(3) receptors and mucosal somatostatin receptor 2 were down-regulated, and the 5-HT-induced somatostatin release from the mucosa/submucosa preparations was significantly reduced in the stress group. Taken together, these results suggest that the 5-HT(3) receptor-mediated somatostatin-dependent secretoinhibitory pathway is suppressed in the water-immersion restraint stressed rats, which may contribute to the acute stress-induced increase in colonic secretion.

Activation of submucosal 5-HT3 receptors elicits a somatostatin-dependent inhibition of ion secretion in rat colon

Background and purpose:  5‐Hydroxytryptamine (5‐HT) is a key regulator of the gastrointestinal system and we have shown that submucosal neuronal 5‐HT3 receptors exerted a novel inhibitory effect on colonic ion transport. The aim of the present study was to investigate the precise mechanism(s) underlying this inhibitory effect.

Rasagiline, an inhibitor of MAO-B, decreases colonic motility through elevating colonic dopamine content

Dopamine (DA) is a negative modulator of gut motility. Monoamine oxidase‐B (MAO‐B) is an important metabolic enzyme degrading DA. Rasagiline, an irreversible MAO‐B inhibitor, is used to treat Parkinson’s disease because of its neuroprotective effect and increasing central DA. However, it is unclear whether MAO‐B exists in the colon and rasagiline increases colonic DA, thereby affecting colonic motility.