Role of 5-hydroxytryptamine type 3 receptors in the regulation of anxiety reactions / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

5-Hydroxytryptamine (5-HT) type 3 receptor (5-HT3R) is the only type of ligand-gated ion channel in the 5-HT receptor family. Through the high permeability of Na+, K+, and Ca2+ and activation of subsequent voltage-gated calcium channels (VGCCs), 5-HT3R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system (CNS). 5-HT3Rs are widely expressed in the medial prefrontal cortex (mPFC), amygdala (AMYG), hippocampus (HIP), periaqueductal gray (PAG), and other brain regions closely associated with anxiety reactions. They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions. 5-HT3Rs mediate the activation of the cholecystokinin (CCK) system in the AMYG, and the γ‍-aminobutyric acid (GABA) "disinhibition" mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons (IINs). In contrast, a 5-HT3R-induced GABA "disinhibition" mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects. 5-HT2R-mediated regulation of anxiety reactions are also activated by 5-HT3R-activated 5-HT release in the HIP and PAG. This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT3Rs. However, given the circuit specific modulation of 5-HT3Rs on emotion, systemic use of 5-HT3R agonism or antagonism alone seems unlikely to remedy anxiety, which deeply hinders the current clinical application of 5-HT3R drugs. Therefore, the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.

Cortical 5-hydroxytryptamine receptor 3A (Htr3a) positive inhibitory neurons: diversity in type and function / 生理学报

Cortical GABAergic inhibitory neurons are composed of three major classes, each expressing parvalbumin (PV), somatostatin (SOM) and 5-hydroxytryptamine receptor 3A (Htr3a), respectively. Htr3a

The Role of Serotonin in Ventricular Repolarization in Pregnant Mice

PURPOSE: The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. MATERIALS AND METHODS: We measured current amplitudes and the expression levels of voltage-gated K⁺ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a(−/−)-NP). RESULTS: During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a(−/−)-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. CONCLUSION: Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents.

Lamotrigine, an antiepileptic drug, inhibits 5-HT₃ receptor currents in NCB-20 neuroblastoma cells

Lamotrigine is an antiepileptic drug widely used to treat epileptic seizures. Using whole-cell voltage clamp recordings in combination with a fast drug application approach, we investigated the effects of lamotrigine on 5-hydroxytryptamine (5-HT)₃ receptors in NCB-20 neuroblastoma cells. Co-application of lamotrigine (1~300 µM) resulted in a concentration-dependent reduction in peak amplitude of currents induced by 3 µM of 5-HT for an IC₅₀ value of 28.2±3.6 µM with a Hill coefficient of 1.2±0.1. These peak amplitude decreases were accompanied by the rise slope reduction. In addition, 5-HT₃-mediated currents evoked by 1 mM dopamine, a partial 5-HT₃ receptor agonist, were inhibited by lamotrigine co-application. The EC₅₀ of 5-HT for 5-HT₃ receptor currents were shifted to the right by co-application of lamotrigine without a significant change of maximal effect. Currents activated by 5-HT and lamotrigine co-application in the presence of 1 min pretreatment of lamotrigine were similar to those activated by 5-HT and lamotrigine co-application alone. Moreover, subsequent application of lamotrigine in the presence of 5-HT and 5-hydroxyindole, known to attenuate 5-HT₃ receptor desensitization, inhibited 5-HT₃ receptor currents in a concentration-dependent manner. The deactivation of 5-HT₃ receptor was delayed by washing with an external solution containing lamotrigine. Lamotrigine accelerated the desensitization process of 5-HT₃ receptors. There was no voltage-dependency in the inhibitory effects of lamotrigine on the 5-HT3 receptor currents. These results indicate that lamotrigine inhibits 5-HT₃-activated currents in a competitive manner by binding to the open state of the channels and blocking channel activation or accelerating receptor desensitization.

Morphologic changes in the spinal cord following intrathecal palonosetron-HCl injection in rats

BACKGROUND: Intravenous palonosetron-HCl, a second-generation antagonist of selective serotonin type 3 (5-HT3) receptors, can prevent chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV). 5-HT3 receptors are abundant in the lower brainstem and the substantia gelatinosa of the spinal cord, which provides a theoretical rationale for neuraxial administration of 5-HT3 receptor antagonists for CINV, PONV, and opioid-induced nausea and vomiting. However, there are no reports of neuraxial administration of palonosetron-HCl. Before neuraxial administration of a drug is accepted for clinical use, its safety must be proven. This study was conducted to determine whether neuraxial administration of palonosetron-HCl produces neurologic injury. METHODS: Male Sprague-Dawley rats under general anesthesia were catheterized intrathecally and the catheter tip was advanced caudally to the L1 vertebra. After 7 days, 20 µl of normal saline (N group, n = 6) or 20 µl (1 µg) of palonosetron-HCl (P group, n = 6) were injected intrathecally once per day for 2 weeks. Neurotoxic changes were evaluated by light microscopy (LM) and electron microscopy (EM) of the spinal cord. Behavioral changes were also evaluated in both groups. RESULTS: One of the N group rats and three of the P group rats demonstrated abnormal behavior during intrathecal drug injection, but otherwise their behavior was normal. The spinal cords of the N group did not have any abnormal findings by LM or EM. The spinal cords of the P group had multiple vacuoles in the white matter by LM, especially in the dorsal funiculus, and EM revealed myelin, axonal, and mitochondrial swelling. CONCLUSIONS: Results suggest that chronic intrathecal administration of palonosetron-HCl produced microscopic morphologic changes in the spinal cords of rats.

Comparison of the efficacy of ramosetron and palonosetron for prevention of postoperative nausea and vomiting in patients undergoing gynecologic oncology surgery

BACKGROUND: Postoperative nausea and vomiting (PONV) is a major concern during the post-surgical period. 5-hydroxy-tryptamine (5-HT3) receptor antagonists may be useful for the prevention of PONV. The recently developed 5-HT3 receptor antagonists, ramosetron and palonosetron, have a greater receptor affinity and a longer elimination half-life. This study was designed to assess the efficacy of palonosetron and ramosetron for prevention of PONV in patients receiving intravenous patient-controlled analgesia (IV-PCA) with opioids after gynecological oncology surgery. METHODS: In this prospective trial, 290 female patients scheduled for elective gynecologic oncology surgery with IV-PCA with opioids were randomized to receive either 0.3 mg ramosetron or 0.075 mg palonosetron intravenously. The occurrence of nausea and vomiting and the use of rescue antiemetics were recorded immediately after the end of surgery, and 0-3 h, 3-24 h, and 24-48 h postoperatively. RESULTS: The total incidence of PONV was similar between the two groups 0-48 h after surgery, but the incidence of nausea was significantly lower in the ramosetron group 24-48 h postoperatively (11.5% vs. 22.0%, P = 0.036). The incidence of vomiting and the use of rescue antiemetics were not significantly different between the two groups during any of the time intervals. Pain intensity scores and total fentanyl consumption were significantly lower in the ramosetron group 24-48 h postoperatively compared to the palonosetron group (P = 0.021, P = 0.041, respectively). CONCLUSIONS: The prophylactic effects of ramosetron and palonosetron on PONV incidence in the postoperative 48 h were similar in patients undergoing gynecologic oncology surgery and those receiving opioid-based IV-PCA.

Clinical Practices and Outcomes on Chemotherapy-Induced Nausea and Vomiting Management in South Korea: Comparison with Asia-Pacific Data of the Pan Australasian Chemotherapy Induced Emesis Burden of Illness Study / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study reported patient outcomes of chemotherapy-induced nausea and vomiting (CINV) prophylaxis for highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) regimens and evaluated its adherence to acute-phase CINV prophylaxis in the Korean population subset of the Pan Australasian Chemotherapy Induced Emesis burden of illness (PrACTICE) study. MATERIALS AND METHODS: This subgroup analysis evaluated 158 Korean patients receiving HEC or MEC and compared the data (wherever possible) with that of 648 patients from the Asia-Pacific (AP) region. Study endpoints included evaluation of primary CINV prophylaxis and adherence to acute-phase CINV prophylaxis in cycle 1 (American Society of Clinical Oncology [ASCO] Quality Oncology Practice Initiative [QOPI]). RESULTS: In South Korea and the AP, a 5-hydroxytryptamine-3 receptor antagonist (5HT₃-RA) prophylaxis for the acute phase was administered to 79/80 patients (98.8%) for HEC and 70/71 patients (98.6%) for MEC regimens (QOPI-1). Triple regimen (corticosteroid–5HT₃-RA–neurokinin 1-RA) was initiated in 46/80 patients (57.5%) for prophylaxis of acute CINV in cycle 1 of HEC (QOPI-3). Double regimen (corticosteroid–5HT₃-RA, with or within NK₁-RA) was initiated in 61/71 patients (83.1%) for control of acute CINV in cycle 1 of MEC a(QOPI-2). CONCLUSION: Active management of CINV is necessary in cycle 1 of HEC in South Korea, despite higher rates than the AP region. Adherence to the international guidelines for CINV prophylaxis requires attention in the acute phase in cycle 1 of the HEC regimen.

comparison of 5-HT3 receptor antagonist and metoclopramide in the patients receiving chemotherapeutic regimens including CMF, CAF and CHOP

Chemotherapy- induced nausea and vomiting [CINV] occur frequently causing problems with an unacceptably high incidence that significantly affect patients' daily functioning and health-related quality of life. The present study was aimed to compare acute CINV for granisetron as 5-HT3 receptor antagonist and metoclopramide in the patients receiving chemotherapeutic regimens including cyclophosphamide and adriamycin. An attempt is made to examine whether it is possible to successfully replace granisetron with metoclopramide in control of acute CINV. A total of 137 patients with breast cancer [78.8%] and lymphoma [17.5%] from two oncology departments in the first course of chemotherapy were enrolled. They received granisetron 3mg/IV and dexamethasone 8mg for the first referring and in the second referring metoclopramid 30mg/IV and dexamethasone 8mg/IV thirty minutes before chemotherapy and metoclopramide 20mg/IV during chemotherapy. The patients recorded the incidence of chemotherapy induced nausea and vomiting [CINV] and other side effects including headache, extra pyramidal manifestations and delayed nausea. Median age of studied patients was 49 +/- 15 year. The patients who received granisetron and dexamethasone had less acute nausea [during the first 24 hours after chemotherapy] than those who received metoclopramide. Also our study showed that controlled CINV episodes in patients who received CMF regimen were better than the regimen including adriamycin [CAF, CHOP] into both granisetron [p=0.06] and metoclopramid [p=0.04]. The most common adverse event related to these drugs was extra pyramidal manifestations for 16 and 10 patients who had received granisetron and metoclopramide respectively. While the number of the patients who had sever delayed CINV [2-7 days after chemotherapy] episodes with granisetron [7 cases] was lower than those who took metoclopramide drug [14 cases]. The number of patients who experienced extrapyramidal manifestations in metoclopramide group was lower than granisetron group. There were not any significant clinically serious adverse events in any patients undergoing chemotherapy due to cancer. Thus, the safety profiles of granisetron and metoclopramide were comparable in this study. The patients who were treated with cyclophosphamide, and adriamycin, the efficacy of dexamethasone and metoclopramide in controlling acute nausea and vomiting nearly equaled to those of granisetron. Thus the present study supports the use of metoclopramide due to its lower cost and nearly the same efficacy and safety compared to granisetron in CMF regimen

Pharmacologic Agents for Chronic Diarrhea

Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly.

Association of 5-HT3B Receptor Gene Polymorphisms with the Efficacy of Ondansetron for Postoperative Nausea and Vomiting

PURPOSE: Postoperative nausea and vomiting (PONV) is a common problem after general anesthesia. Although 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists have significantly reduced PONV, over 35% of patients treated with ondansetron can experience PONV. In this study, we investigated whether the Y129S and -100_-102AAG deletion polymorphisms of the 5-HT3B receptor gene affect the efficacy of ondansetron in preventing PONV. MATERIALS AND METHODS: Two hundred and forty-five adult patients who underwent laparoscopic cholecystectomy were enrolled. Ondansetron 0.1 mg/kg was intravenously administered 30 minutes before the end of surgery. Genomic DNA was prepared from blood samples using a nucleic acid isolation device. Both the Y129S variant and the -100_-102AAG deletion variant were screened for using a single base primer extension assay and a DNA direct sequencing method, respectively. The relationship between genetic polymorphisms and clinical outcomes of ondansetron treatment was investigated. RESULTS: Among the 5-HT3B AAG deletion genotypes, the incidence of PONV was higher in patients with the homomutant than with other genotypes during the first 2 hours after surgery (p=0.02). There were no significant differences in the incidence of PONV among genotypes at 2-24 hours after surgery. In the Y129S variants of the 5-HT3B receptor gene, there were no significant differences in the incidence of PONV among genotypes during the first 2 hours and at 2-24 hours after surgery. CONCLUSION: The response to ondansetron for PONV was significantly influenced by the -100_-102AAG deletion polymorphisms of the 5-HT3B gene. Thus, the -100_-102AAG deletion variants may be a pharmacogenetic predictor for responsiveness to ondansetron for PONV.

Distribution of 5-HT3, 5-HT4, and 5-HT7 Receptors Along the Human Colon

BACKGROUND/AIMS: Several disorders of the gastrointestinal tract are associated with abnormal serotonin (5-HT) signaling or metabolism where the 5-HT3 and 5-HT4 receptors are clinically relevant. The aim was to examine the distribution of 5-HT3, 5-HT4, and 5-HT7 receptors in the normal human colon and how this is associated with receptor interacting chaperone 3, G protein coupled receptor kinases, and protein LIN-7 homologs to extend previous observations limited to the sigmoid colon or the upper intestine. METHODS: Samples from ascending, transverse, descending, and sigmoid human colon were dissected into 3 separate layers (mucosa, longitudinal, and circular muscles) and ileum samples were dissected into mucosa and muscle layers (n = 20). Complementary DNA was synthesized by reverse transcription from extracted RNA and expression was determined by quantitative or end point polymerase chain reaction. RESULTS: The 5-HT3 receptor subunits were found in all tissues throughout the colon and ileum. The A subunit was detected in all samples and the C subunit was expressed at similar levels while the B subunit was expressed at lower levels and less frequently. The 5-HT3 receptor E subunit was mainly found in the mucosa layers. All splice variants of the 5-HT4 and 5-HT7 receptors were expressed throughout the colon although the 5-HT4 receptor d, g, and i variants were expressed less often. CONCLUSIONS: The major differences in 5-HT receptor distribution within the human colon are in relation to the mucosa and muscular tissue layers where the 5-HT3 receptor E subunit is predominantly found in the mucosal layer which may be of therapeutic relevance.

Comparison of electroacupuncture and moxibustion on brain-gut function in patients with diarrhea-predominant irritable bowel syndrome: A randomized controlled trial / 中国结合医学杂志

<p><b>OBJECTIVE</b>To compare the effects of electroacupuncture (EA) and moxibustion therapies on patients with diarrhea-predominant irritable bowel syndrome (D-IBS).</p><p><b>METHODS</b>A total of 60 D-IBS patients were randomly allocated to the EA group (30 cases) and moxibustion group (30 cases). Before and after treatment, the gastrointestinal symptoms and psychological symptoms were scored by Visual Analogue Scale, Bristol Stool Form Scale, Hamilton Anxiety Rating Scale (HAMA), and Hamilton Depression Rating Scale (HAMD); the expressions of 5-hydroxytryptamine (5-HT), 5-HT3 receptor (5-HT3R), and 5-HT4 receptor (5-HT4R) in the sigmoid mucosal tissue were measured by immunohistochemical staining. Additionally, the effects on the functional brain areas of the anterior cingulate cortex (ACC), insular cortex (IC) and prefrontal cortex (PFC) were observed by functional magnetic resonance imaging.</p><p><b>RESULTS</b>Compared with before treatment, both EA and moxibustion groups reported significant improvements in abdominal pain and abdominal bloating after treatment (P<0.01 or P<0.05). The moxibustion group reported greater improvements in defecation emergency, defecation frequency, and stool feature than the EA group (P<0.01). Both HAMA and HAMD scores were significantly decreased in the moxibustion group than in the EA group (P<0.01). Both groups demonstrated significantly reduced expressions of 5-HT, 5-HT3R and 5-HT4R in the colonic mucosa after treatment (P<0.01), with a greater reduction of 5-HT in the moxibustion group (P<0.05). Finally, decreased activated voxel values were observed in the left IC, right IC and PFC brain regions of patients in the moxibustion group under stimulation with 150 mL colorectal distension after treatment (P<0.05 or P<0.01), while in the EA group only PFC area demonstrated a reduction (P<0.05).</p><p><b>CONCLUSION</b>Moxibustion can significantly improve the symptoms of D-IBS, suggesting that moxibustion may be a more effective therapy than EA for D-IBS patients.</p>

Spinal 5-HT3AR contributes to BmK I-induced inflammatory pain in rats / 生理学报

Subcutaneous injection of BmK I could be adopted to well establish a novel pain model. Moreover, 5-hydroxytryptamine (serotonin, 5-HT) receptor is involved in regulating animal pain-related behaviors. However, the underlying mechanism of 5-HT3R on BmK I-induced pain remains unclear. Animal behavioral testing, RT-PCR and Western blotting were used to yield the following results: first, intraplantar (i.pl.) injection of BmK I (10 μg) induced elevated mRNA and protein levels of 5-HT3AR in bilateral L4-L5 spinal cord; Second, intrathecal (i.t.) injection of ondansetron (a specific antagonist of 5-HT3AR) reduced spontaneous pain responses, attenuated unilateral thermal and bilateral mechanical hypersensitivity elicited by BmK I; Microglia could be activated by BmK I (i.pl.) in both sides of L4-L5 spinal cord, and this effect was reversed by intrathecal pre-treatment with 5-HT3AR antagonist. Meanwhile, the 5-HT3AR in L4-L5 spinal cord was almost co-localized with NeuN (a marker of nerve cell), but not co-expressed with Iba-1 (a marker of microglia). Finally, the expression level of CX3CL1 and CX3CR1 was reduced by intrathecal pre-treatment with ondansetron. Our results indicate that both 5-HT3AR signaling pathway and microglia are activated in the process of induction and maintenance of BmK I-induced pain nociception. Meanwhile, our results suggest that the neuronal 5-HT3AR may communicate with microglia indirectly via CX3CL1 which is involved in regulating the BmK I-induced hyperalgesia and sensitization.

Ginger and Its Pungent Constituents Non-Competitively Inhibit Serotonin Currents on Visceral Afferent Neurons

Nausea and emesis are a major side effect and obstacle for chemotherapy in cancer patients. Employ of antiemetic drugs help to suppress chemotherapy-induced emesis in some patients but not all patients. Ginger, an herbal medicine, has been traditionally used to treat various kinds of diseases including gastrointestinal symptoms. Ginger is effective in alleviating nausea and emesis, particularly, for cytotoxic chemotherapy drug-induced emesis. Ginger-mediated antiemetic effect has been attributed to its pungent constituents-mediated inhibition of serotonin (5-HT) receptor activity but its cellular mechanism of action is still unclear. Emetogenic chemotherapy drugs increase 5-HT concentration and activate visceral vagal afferent nerve activity. Thus, 5-HT mediated vagal afferent activation is essential to provoke emesis during chemotherapy. In this experiment, water extract of ginger and its three major pungent constituent's effect on 5-HT-evoked responses were tested on acutely dispersed visceral afferent neurons with patch-clamp methods. The ginger extract has similar effects to antiemetic drug ondansetron by blocking 5-HT-evoked responses. Pungent constituents of the ginger, [6]-shogaol, [6]-gingerol, and zingerone inhibited 5-HT responses in a dose dependent manner. The order of inhibitory potency for these compounds were [6]-shogaol>[6]-gingerol>zingerone. Unlike well-known competitive 5-HT3 receptor antagonist ondansetron, all tested ginger constituents acted as non-competitive antagonist. Our results imply that ginger and its pungent constituents exert antiemetic effects by blocking 5-HT-induced emetic signal transmission in vagal afferent neurons.

Multicenter nonrandomized trial of ramosetron versus palonosetron in controlling chemotherapy-induced nausea and vomiting for colorectal cancer

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) have a negative impact on patients' quality of life and frequently pointed to as a major factor for treatment abandonment. Serotonin (5-HT3) receptor antagonist is considered as key treatment for CINV. Ramosetron and palonosetron are recently developed 5-HT3 receptor antagonists and known as more superior than other first-generation 5-HT3 receptor antagonists. The purpose of this study was to compare the efficacy of ramosetron and palonosetron and determine which drug is more effective for prevention of CINV. METHODS: Colorectal cancer patients treated with chemotherapy were enrolled consecutively. Patients were assigned to receive intravenous injection of ramosetron 0.3 mg or palonosetron 0.25 mg at 30 minutes before initiation of moderately emetogenic chemotherapy. Ramosetron group added oral administration of 0.1 mg ramosetron on the second and third days of chemotherapy. Efficacy parameter consisted of nausea and vomiting. RESULTS: Ninety-one patients received ramosetron and 89 patients received palonosetron. Presentation of vomiting and nausea symptoms was not significantly different between the two groups during acute (0-24 hours) and delayed period (after 24 hours). CONCLUSION: The incidence of CINV between the ramosetron and the palonosetron group has not shown any difference during acute, delayed, and overall period.

The relationship between perioperative nausea and vomiting and serum serotonin concentrations in patients undergoing cesarean section under epidural anesthesia / 대한마취과학회지

BACKGROUND: Serotonin-also known as 5-hydroxytryptamine or 5-HT-can induce nausea and vomiting (NV) by peripheral mechanisms via the activation of 5-HT3 receptors. In this study, we observed perioperative NV, including intraoperative NV, and changes in serum 5-HT concentrations. We evaluated the relationship between perioperative NV and serum 5-HT levels in patients undergoing cesarean section under epidural anesthesia, and carried out a pilot study to determine if further studies on a larger scale were justified. METHODS: Twenty-eight patients who were scheduled for cesarean section under epidural anesthesia were included in the study. Patients were assigned to 2 groups according to the occurrence of NV after induction, i.e., an NV-positive or an NV-negative group. Serum 5-HT concentrations were measured before induction, at the time that NV occurred (in the case of the NV-positive group) or 5 min after the umbilical cord clamping (in the case of the NV-negative group) during surgery, and at 2 h postoperatively. RESULTS: NV occurred in 10 of the 28 patients. No significant differences in serum 5-HT concentrations were found within or between the two groups. CONCLUSIONS: This study suggests that there is no correlation between serum 5-HT concentration and the occurrence of perioperative NV in patients undergoing cesarean section under epidural anesthesia, and the findings do not seem to support further investigations regarding a possible relationship between serum 5-HT concentration and perioperative NV.

Analgesic effects of palonosetron in the intravenous propofol injection / 대한마취과학회지

BACKGROUND: Propofol is a good induction agent, but it has the disadvantage of causing pain on intravenous injection. The incidence of propofol-induced pain is approximately 70%. Palonosetron is a novel second-generation 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist. We presumed that palonosetron would be effective in reducing the occurrence of propofol-induced pain based on similar mechanisms to other 5-HT3 receptor antagonists. METHODS: Eighty patients were randomized to either Group N (0.9% sodium chloride [normal saline] 2 ml, n = 40) or Group P (palonosetron 0.075 mg, 2 ml, n = 40). Patients were intravenously given a 2 ml pretreatment solution, containing either palonosetron 0.075 mg or normal saline. Following pretreatment with 2 ml of palonosetron 0.075 mg or normal saline, we manually occluded venous drainage midarm with the help of an assistant. One minute later, we released the occlusion of venous drainage. This was followed by a 5-second propofol injection at 25% of the total calculated doses. Patients were then interviewed about whether or not they experienced propofol-induced pain. RESULTS: Overall, the incidence of propofol-induced pain was 60% in the normal saline group and 27.5% in the palonosetron group. No patients in the palonosetron group experienced severe pain. The incidence of propofol-induced pain was significantly lower in the palonosetron group compared to the normal saline group (P < 0.01). CONCLUSIONS: Following pretreatment with palonosetron, 72.5% of patients experienced a decrease in the occurrence of propofol-induced pain.

Anxiolytic-like effect of N-n-butyl-3-methoxyquinoxaline-2-carboxamide (6o) in experimental mouse models of anxiety.

The present research was designed to explore the anxiolytic-like activity of a novel 5-HT3 receptor antagonist (6o) in experimental mouse models of anxiety. The anxiolytic activity of '6o' at (1 and 2 mg/kg, ip) was evaluated in mice by using a battery of behavioural tests of anxiety such as elevated plus maze (EPM), light/dark aversion test, hole board (HB) and open field test (OFT) with diazepam (2 mg/kg, ip) as a standard anxiolytic. None of the tested doses of '6o' affected the base line locomotion. Compound '6o' (2 mg/kg, ip) and diazepam (2mg/kg, ip) significantly increased the percentage of both time spent and open arm entries in the EPM test. Compound '6o' in (1 mg/kg, ip) dose was only able to affect the percentage time spent in open arm significantly in the EPM test. In the light and dark test, compound '6o' (2 mg/kg, ip) and diazepam (2mg/kg, ip) significantly increased the total time spent in light compartment as well as number of transitions from one compartment to other and number of square crossed. Compound '6o' (1 and 2 mg/kg, ip) and diazepam (2 mg/kg, ip) also significantly increased number of head dips and number of squares crossed, whereas significantly decreased the head dipping latency in HB test as compared to vehicle control group. In addition, '6o' in both the doses and diazepam (2mg/kg, ip) significantly increased the ambulation scores (squares crossed) in OFT however, there was no significant effect of '6o' (1 and 2 mg/kg, ip) and diazepam (2 mg/kg, ip) on rearing scores. To conclude compound '6o' exhibited an anxiolytic-like effect in animal models of anxiety.

Efficacy of the oral neurokinin-1 receptor antagonist aprepitant administered with ondansetron for the prevention of postoperative nausea and vomiting / 대한마취과학회지

BACKGROUND: 5-HT3 receptor antagonist, dexamethasone and droperidol were used for the prevention of postoperative nausea and vomiting (PONV). Recently, neurokinin-1 (NK1) antagonist has been used for PONV. We evaluated the effect of oral aprepitant premedication in addition to ondansetron. METHODS: A total 90 patients scheduled for elective rhinolaryngological surgery were allocated to three groups (Control, Ap80, Ap125), each of 30 at random. Ondansetron 4 mg was injected intravenously to all patients just before the end of surgery. On the morning of surgery, 80 mg and 125 mg aprepitant were additionally administered into the Ap80 group and Ap125 group, respectively. The rhodes index of nausea, vomiting and retching (RINVR) was checked at 6 hr and 24 hr after surgery. RESULTS: Twelve patients who used steroids unexpectedly were excluded. Finally 78 patients (control : Ap80 : Ap125 = 24 : 28 : 26) were enrolled. Overall PONV occurrence rate of Ap125 group (1/26, 3.9%) was lower (P = 0.015) than the control group (7/24, 29.2%) at 6 hr after surgery. The nausea distress score of Ap125 group (0.04 +/- 0.20) was lower (P = 0.032) than the control group (0.67 +/- 1.24) at 6 hr after surgery. No evident side effect of aprepitant was observed. CONCLUSIONS: Oral aprepitant 125 mg can be used as combination therapy for the prevention of PONV.

Effects of Palonosetron, a 5-HT3 Receptor Antagonist, on Mechanical Allodynia in a Rat Model of Postoperative Pain

BACKGROUND: 5-hydroxytryptamine 3 (5-HT3) receptors have been known to be associated with the modulation of nociceptive transmission. However, it is uncertain whether 5-HT3 plays a role in the antinociceptive or pronociceptive pathway for incisional pain. In this study, we evaluated the effects of palonosetron, a 5-HT3 receptor antagonist, on incisional pain in rats when administered intrathecally or intraplantarly. METHODS: An intrathecal catheter was implanted through the cisterna magna and placed in the intrathecal space of rats. An incision in the plantaris muscle of the right hind paw was done under anesthesia with sevoflurane. Withdrawal thresholds were evaluated with the von Frey filament after 2 hours. Palonosetron (0.5 and 0.1 microg intrathecally; 0.5 microg intraplantarly) was administered and the thresholds were observed for 4 hours. RESULTS: Mechanical hypersensitivity developed after the incision. Intrathecal palonosetron (0.5 microg and 0.1 microg) did not alter the paw withdrawal threshold. Intraplantar palonosetron (0.5 microg) also did not change the paw withdrawal threshold. CONCLUSIONS: Intrathecal and intraplantar palonosetron (0.5 microg) had no effect on modulating the mechanical hypersensitivity in the incisional pain model of rats.