Selective Serotonin Reuptake Inhibitors Modify Physiological Gastrointestinal Motor Activities via 5-HT2c Receptor and Acyl Ghrelin

Fujitsuka, Naoki; Asakawa, Akihiro; Hayashi, Masatomo; Sameshima, Marie; Amitani, Haruka; Kojima, Shinya; Fujimiya, Mineko; Inui, Akio

doi:10.1016/j.biopsych.2008.10.031

Cited by 104 publications

(96 citation statements)

References 48 publications

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“…In addition, it is reported that emetogenic agents, such as cisplatin, apomorphine, and copper sulfate, prevent GI motility and gastric emptying in experimental animals and humans (25,26). In fact, it is reported that SSRIs inhibit GI motor activity through 5-HT 2C receptors (27). Our results also show that paroxetine delays gastric emptying in rats (Fig.…”

Section: Discussionsupporting

confidence: 70%

Anti-emetic Effect of Mosapride Citrate Hydrate, a 5-HT4 Receptor Agonist, on Selective Serotonin Reuptake Inhibitors (SSRIs)-Induced Emesis in Experimental Animals

2013

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Abstract. Although selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, they frequently cause gastrointestinal adverse effects, such as nausea and emesis. In the present study, we investigated the anti-emetic effect of mosapride, a 5-HT 4 receptor agonist, on SSRIs-induced emesis in Suncus murinus and dogs. We also examined the effect of mosapride on SSRIs-induced delay in gastric emptying and increase in gastric vagal afferent activity in rats. Oral administration of paroxetine, but not its subcutaneous administration, dose-dependently caused emesis in both animals. Mosapride inhibited paroxetine-induced emesis in Suncus murinus and dogs with ID 50 values of 7.9 and 1.1 mg/kg, respectively. The anti-emetic effect of mosapride was partially inhibited by SB207266, a selective 5-HT 4 antagonist. Intragastric administration of paroxetine increased gastric vagal afferent discharge in anesthetized rats. Mosapride failed to suppress this increase. On the other hands, mosapride improved the delay in gastric emptying caused by paroxetine in rats. We have shown in this study that oral administration of SSRIs causes emesis and activates gastric vagal afferent activity in experimental animals and that mosapride inhibits SSRIs-induced emesis, probably via improvement of SSRIs-induced delay in gastric emptying. These findings highlight the promising potential of mosapride as an anti-emetic agent.

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Section: Discussionsupporting

confidence: 70%

Anti-emetic Effect of Mosapride Citrate Hydrate, a 5-HT4 Receptor Agonist, on Selective Serotonin Reuptake Inhibitors (SSRIs)-Induced Emesis in Experimental Animals

2013

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“…Rikkunshito was found to improve anorexia symptoms in a double-blind study of patients with functional dyspepsia (29). Additionally, increasing evidence from experimental animal models has shown that rikkunshito ameliorates several types of anorexia (23,24,57). It has been reported that with rikkushito there is an increase in the secretion of the orexigenic hormone ghrelin by the inhibition of 5-HT2B/2C receptors, an enhancement of ghrelin receptor (GHSR) signaling efficiency, and a facilitation of gastric emptying and gastric adaptive relaxation, all of which may contribute to ameliorate anorexia (24,32,57,60,64).…”

mentioning

confidence: 99%

New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line

Terawaki

Sawada²,

Kashiwase

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Cancer cachexia (CC), a syndrome characterized by anorexia and body weight loss due to low fat-free mass levels, including reduced musculature, markedly worsens patient quality of life. Although stomach cancer patients have the highest incidence of cachexia, few experimental models for the study of stomach CC have been established. Herein, we developed stomach CC animal models using nude rats subcutaneously implanted with two novel cell lines, i.e., MKN45c185, established from the human stomach cancer cell line MKN-45, and 85As2, derived from peritoneal dissemination of orthotopically implanted MKN45c185 cells in mice. Both CC models showed marked weight loss, anorexia, reduced musculature and muscle strength, increased inflammatory markers, and low plasma albumin levels; however, CC developed earlier and was more severe in rats implanted with 85As2 than in those implanted with MKN45cl85. Moreover, human leukemia inhibitory factor (LIF), a known cachectic factor, and hypothalamic orexigenic peptide mRNA levels increased in the models, whereas hypothalamic anorexigenic peptide mRNA levels decreased. Surgical removal of the tumor not only abolished cachexia symptoms but also reduced plasma LIF levels to below detectable limits. Importantly, oral administration of rikkunshito, a traditional Japanese medicine, substantially ameliorated CC-related anorexia and body composition changes. In summary, our novel peritoneal dissemination-derived 85As2 rat model developed severe cachexia, possibly caused by LIF from cancer cells, that was ameliorated by rikkunshito. This model should provide a useful tool for further study into the mechanisms and treatment of stomach CC. cachexia; leukemia inhibitory factor; rikkunshito; stomach cancer model; anorexia CANCER CACHEXIA, A MULTIFACTORIAL SYNDROME characterized by anorexia and the loss of body weight, adipose tissue, and skeletal muscle, is observed in 80% of advanced cancer patients and accounts for at least 20% of cancer-related deaths (20,35,42). This syndrome causes not only poor quality of life (QOL) but also poor responses to chemotherapy, highlighting the need for improved cancer cachexia treatments. Weight loss, the most prominent clinical feature of cachexia, is observed in 30 -80% of cancer patients, depending on tumor type. For example, weight loss occurs at a very high frequency (83%) in stomach and pancreatic cancer patients but is less prominent in patients with breast cancer, acute nonlymphocytic leukemia, and sarcomas (35). Although cachexia strongly impacts the success of therapeutic treatments, the mechanisms underlying this syndrome are not fully understood. Stomach cancer patients in particular have the highest incidence of cachexia; however, few experimental models for the study of stomach cancer cachexia have been established (4,14,66).A useful cachexia model must meet three of the following five diagnostic criteria in addition to weight loss: anorexia, decreased muscle strength, fatigue, low fat-free mass (FFM) index, and abnormal biochemistry (anemia, in...

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“…In another study conducted in patients with advanced breast cancer, concomitant administration of rikkunshito with antiemetics such as granisetron proved to be effective against the anorexia and vomiting induced by anticancer drugs [23]. In a recent report, rikkunshito administration was shown to stimulate peripheral ghrelin secretion in rats with anorexia induced by cisplatin or selective serotonin reuptake inhibitors [16,33]. Furthermore, oral administration of rikkunshito was shown to stimulate the secretion of ghrelin from the stomach in healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, these reports demonstrated that the oral administration of rikkunshito ameliorated anorexia and gastrointestinal dysmotility in rats treated with either cisplatin or selective serotonin reuptake inhibitors, suggesting that 5-HT2 receptor antagonism could be at least partially responsible for the effect of rikkunshito in improving appetite loss [16,33]. Rikkunshito attenuated cisplatin-induced gastrointestinal dysfunction through the improvement of ghrelin release that occurred via the 5-HT2B/2C antagonistic action of flavonoids contained in rikkunshito [16].…”

Section: Error Bars Represent Sdsmentioning

confidence: 97%

“…Recently, some reports have demonstrated that rikkunshito induces endogenous ghrelin secretion via its flavonoids, which antagonize 5-HT2B and 5-HT2c receptors [16,33]. Furthermore, these reports demonstrated that the oral administration of rikkunshito ameliorated anorexia and gastrointestinal dysmotility in rats treated with either cisplatin or selective serotonin reuptake inhibitors, suggesting that 5-HT2 receptor antagonism could be at least partially responsible for the effect of rikkunshito in improving appetite loss [16,33].…”

Section: Error Bars Represent Sdsmentioning

confidence: 99%

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Effect of rikkunshito, a Japanese herbal medicine, on gastrointestinal symptoms and ghrelin levels in gastric cancer patients after gastrectomy

et al. 2012

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Background Gastric cancer patients who undergo gastrectomy suffer from a post-gastrectomy syndrome that includes weight loss, dumping syndrome, reflux esophagitis, alkaline gastritis, and finally malnutrition. It is important to ameliorate the post-gastrectomy symptoms to restore postoperative quality of life (QoL). The aim of this study was to investigate the effect of rikkunshito, a Japanese herbal medicine, on postoperative symptoms and ghrelin levels in gastric cancer patients after gastrectomy. Methods Twenty-five patients who had undergone gastrectomy received 2.5 g of rikkunshito before every meal for 4 weeks, and a drug withdrawal period was established for the next 4 weeks. Changes in gastrointestinal hormones, including ghrelin, and appetite visual analog scale scores were measured, and QoL was estimated by using the European Organization for Research and Treatment of Cancer core questionnaire QLQ-C30. The Dysfunction After Upper Gastrointestinal Surgery for Cancer (DAUGS) scoring system was used to evaluate gastrointestinal symptoms after gastrectomy. Results Sixteen men and nine women (mean age 61.9 years) were enrolled in the study. All patients had either stage I (n = 24) or II (n = 1) disease and had undergone either distal gastrectomy (n = 17) or total gastrectomy (n = 8) by a laparoscopy-assisted approach. The mean ratio of the acyl-/total ghrelin concentration increased significantly after rikkunshito administration (Pre: 7.8 ± 2.1, 4 weeks: 10.5 ± 1.7 %, p = 0.0026). The total DAUGS score, as well as the scores reflecting limited activity due to decreased food consumption, reflux symptoms, dumping symptoms, and nausea and vomiting significantly improved after rikkunshito administration. Conclusions The present study demonstrated a significant attenuation of gastrointestinal symptoms after gastrectomy by treatment with rikkunshito. Rikkunshito is potentially useful to minimize gastrointestinal symptoms after gastrectomy.

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Selective Serotonin Reuptake Inhibitors Modify Physiological Gastrointestinal Motor Activities via 5-HT2c Receptor and Acyl Ghrelin

Cited by 104 publications

References 48 publications

Anti-emetic Effect of Mosapride Citrate Hydrate, a 5-HT4 Receptor Agonist, on Selective Serotonin Reuptake Inhibitors (SSRIs)-Induced Emesis in Experimental Animals

Anti-emetic Effect of Mosapride Citrate Hydrate, a 5-HT4 Receptor Agonist, on Selective Serotonin Reuptake Inhibitors (SSRIs)-Induced Emesis in Experimental Animals

New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line

Effect of rikkunshito, a Japanese herbal medicine, on gastrointestinal symptoms and ghrelin levels in gastric cancer patients after gastrectomy

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