ABSTRACT
Gut-derived 5-hydroxytryptamine (5-HT) is well known for its role in mediating colonic motility function. However, it is not very clear whether brain-derived 5-HT is involved in the regulation of colonic motility. In this study, we used central 5-HT knockout (KO) mice to investigate whether brain-derived 5-HT mediates colonic motility, and if so, whether it involves oxytocin (OT) production in the hypothalamus and OT receptor in the colon. Colon transit time was prolonged in KO mice. The OT levels in the hypothalamus and serum were decreased significantly in the KO mice compared to wild-type (WT) controls. OT increased colonic smooth muscle contraction in both KO and WT mice, and the effects were blocked by OT receptor antagonist and tetrodotoxin but not by hexamethonium or atropine. Importantly, the OT-induced colonic smooth muscle contraction was decreased significantly in the KO mice relative to WT. The OT receptor expression of colon was detected in colonic myenteric plexus of mice. Central 5-HT is involved in the modulation of colonic motility which may modulate through its regulation of OT synthesis in the hypothalamus. Our results reveal a central 5-HT - hypothalamus OT - colonic OT receptor axis, providing a new target for the treatment of brain-gut dysfunction.
Subject(s)
Colon/physiology , Gastrointestinal Motility , Hypothalamus/metabolism , Oxytocin/metabolism , Receptors, Oxytocin/metabolism , Serotonin/physiology , Animals , Colon/metabolism , Female , Male , Mice , Mice, Knockout , Muscle Contraction , Oxytocin/blood , Pituitary Gland/metabolism , Tryptophan Hydroxylase/geneticsABSTRACT
Colonic dysmotility occurs in diabetes and blood plasma interleukin (IL)-6 levels are significantly elevated in type 1 diabetes mellitus. The aim of this study was to investigate whether IL-6 and the IL-6 receptor pathway mediates colonic dysfunction in type 1 diabetes mellitus. Male SD rats were treated with a single intraperitoneally injected dose of streptozotocin (STZ), and those displaying sustained high blood glucose were selected as diabetes mellitus models. Longitudinal muscle strips of colon were prepared to monitor colonic contraction in vitro. Contractile responses of strips of colon were recorded following treatment with IL-6 in control animals, and following anti IL-6 antibody treatment in STZ-induced diabetes in rats. Concentration of IL-6 in plasma and colon were determined by ELISA. Expressions of IL-6 α-receptor and IL-6 ß-receptor in colon tissues were determined by immunohistochemistry or Western blot analysis. The non-diabetes rats treated with IL-6 and the untreated diabetes rats showed increased contraction of distal colon, whereas the diabetes rats treated with anti-IL-6 antibody showed decreased contraction of distal colon compared with the untreated diabetes rats. The IL-6 levels of plasma but not colon increased in diabetes rats. The expression of IL-6 α-receptor increased in diabetes rats. These results indicate that diabetes rats show an increase in the contractions of distal colon partly via the IL-6-IL-6 receptor pathway.
Subject(s)
Colon/drug effects , Cytokine Receptor gp130/agonists , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 1/physiopathology , Gastrointestinal Motility/drug effects , Interleukin-6 Receptor alpha Subunit/agonists , Interleukin-6/pharmacology , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Animals , Carbachol/pharmacology , Colon/metabolism , Colon/physiopathology , Cytokine Receptor gp130/metabolism , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Type 1/blood , Dose-Response Relationship, Drug , In Vitro Techniques , Interleukin-6/blood , Interleukin-6 Receptor alpha Subunit/metabolism , Male , Muscle, Smooth/metabolism , Muscle, Smooth/physiopathology , Rats, Sprague-Dawley , Signal Transduction/drug effects , Time FactorsABSTRACT
AIM: To investigate whether cold water intake into the stomach affects colonic motility and the involvement of the oxytocin-oxytocin receptor pathway in rats. METHODS: Female Sprague Dawley rats were used and some of them were ovariectomized. The rats were subjected to gastric instillation with cold (0-4â °C, cold group) or room temperature (20-25â °C, control group) saline for 14 consecutive days. Colon transit was determined with a bead inserted into the colon. Colonic longitudinal muscle strips were prepared to investigate the response to oxytocin in vitro. Plasma concentration of oxytocin was detected by ELISA. Oxytocin receptor expression was investigated by Western blot analysis. Immunohistochemistry was used to locate oxytocin receptors. RESULTS: Colon transit was slower in the cold group than in the control group (P < 0.05). Colonic smooth muscle contractile response to oxytocin decreased, and the inhibitory effect of oxytocin on muscle contractility was enhanced by cold water intake (0.69 ± 0.08 vs 0.88 ± 0.16, P < 0.05). Atosiban and tetrodotoxin inhibited the effect of oxytocin on colonic motility. Oxytocin receptors were located in the myenteric plexus, and their expression was up-regulated in the cold group (P < 0.05). Cold water intake increased blood concentration of oxytocin, but this effect was attenuated in ovariectomized rats (286.99 ± 83.72 pg/mL vs 100.56 ± 92.71 pg/mL, P < 0.05). However, in ovariectomized rats, estradiol treatment increased blood oxytocin, and the response of colonic muscle strips to oxytocin was attenuated. CONCLUSION: Cold water intake inhibits colonic motility partially through oxytocin-oxytocin receptor signaling in the myenteric nervous system pathway, which is estrogen dependent.
Subject(s)
Cold Temperature , Colon/innervation , Gastrointestinal Motility/drug effects , Muscle, Smooth/innervation , Myenteric Plexus/drug effects , Oxytocin/pharmacology , Receptors, Oxytocin/agonists , Stress, Psychological/drug therapy , Water , Animals , Dose-Response Relationship, Drug , Drinking , Estradiol/pharmacology , Estrogen Replacement Therapy , Female , Hormone Antagonists/pharmacology , Myenteric Plexus/metabolism , Myenteric Plexus/physiopathology , Ovariectomy , Oxytocin/blood , Rats, Sprague-Dawley , Receptors, Oxytocin/antagonists & inhibitors , Receptors, Oxytocin/metabolism , Signal Transduction/drug effects , Stress, Psychological/blood , Stress, Psychological/physiopathology , Stress, Psychological/psychology , Time FactorsABSTRACT
Colonic dysmotility occurs in diabetes and the patients exhibit diarrhea or constipation. The pathogenetic mechanisms underlying colonic dysmotility in diabetic patients remain poorly understood. The effects of ß-arrestin2 on colonic contraction in diabetic rats were investigated for the first time. Male SD rats were treated with a single intraperitoneally injected dose of streptozotocin, and those displaying sustained high blood glucose were selected as diabetes mellitus models. Longitudinal muscle strips of the distal colon were prepared to monitor contraction of the colon in vitro. Expression of ß-arrestin2 was investigated by Western blot analysis. Anti-ß-arrestin2 antibody had no direct effect on the contraction of distal colonic strips in both normal and diabetic rats. Carbachol-induced contractions of distal colonic strips were higher in diabetic rats than in normal rats. Anti-ß-arrestin2 antibody partly blocked carbachol-induced increases of distal colonic strips in diabetic rats. The expression level of ß-arrestin2 protein in the colon was higher in diabetic rats than in normal rats. These results suggest that ß-arrestin2 is involved in the increase of distal colonic contraction in diabetic rats.
