Dietary Tryptophan Supplementation Alters Fat and Glucose Metabolism in a Low-Birthweight Piglet Model.

Low birthweight (LBW) is associated with metabolic complications, such as glucose and lipid metabolism disturbances in early life. The objective of this study was to assess: (1) the effect of dietary tryptophan (Trp) on glucose and fat metabolism in an LBW piglet model, and (2) the role peripheral 5-hydroxytryptamine type 3 (5HT3) receptors in regulating the feeding behavior in LBW piglets fed with Trp-supplemented diets. Seven-day-old piglets were assigned to 4 treatments: normal birthweight-0%Trp (NBW-T0), LBW-0%Trp (LBW-T0), LBW-0.4%Trp (LBW-T0.4), and LBW-0.8%Trp (LBW-T0.8) for 3 weeks. Compared to LBW-T0, the blood glucose was decreased in LBW-T0.8 at 60 min following the meal test, and the triglycerides were lower in LBW-T0.4 and LBW-T0.8. Relative to LBW-T0, LBW-T0.8 had a lower transcript and protein abundance of hepatic glucose transporter-2, a higher mRNA abundance of glucokinase, and a lower transcript of phosphoenolpyruvate carboxykinase. LBW-T0.4 tended to have a lower protein abundance of sodium-glucose co-transporter 1 in the jejunum. In comparison with LBW-T0, LBW-T0.4 and LBW-T0.8 had a lower transcript of hepatic acetyl-CoA carboxylase, and LBW-T0.4 had a higher transcript of 3-hydroxyacyl-CoA dehydrogenase. Blocking 5-HT3 receptors with ondansetron reduced the feed intake in all groups, with a transient effect on LBW-T0, but more persistent effect on LBW-T0.8 and NBW-T0. In conclusion, Trp supplementation reduced the hepatic lipogenesis and gluconeogenesis, but increased the glycolysis in LBW piglets. Peripheral serotonin is likely involved in the regulation of feeding behavior, particularly in LBW piglets fed diets supplemented with a higher dose of Trp.

Identification and molecular study on the interaction of Schisandrin C with human 5-HT3A receptor.

Schisandrin C (Sch C) is one of the main components of Schisandra chinensis (Schisandra). Since the olden times, Schisandra has been used as a traditional herbal medicine in Asia. Recent studies have shown that Schisandra is effective against irritable bowel syndrome (IBS) in an animal model and affects IBS through the 5-HT3A pathway in the IBS rat model. However, there lacks fundamental research on the interaction of specific components of Schisandra with the 5-HT3A receptor for the treatment of IBS. We hypothesized that a component of Schisandra binds to the 5-HT3A receptor and identified Sch C via a screening work using two electrode-voltage clamps (TEVC). Thus, we aimed to elucidate the neuropharmacological actions between Sch C and the 5-HT3A receptor at molecular and cellular levels. Co-treatment of Sch C with 5-HT inhibited I5-HT in a reversible, concentrate-dependent, like-competition, and voltage-independent manner, and IC50 values of Sch C. Besides, the main binding positions of Sch C were identified through 3D modeling and point mutation were V225A and V288Y on 5-HT3A receptor. Thus, we suggest the potential of Sch C in treating IBS in a manner that suppresses excessive neuronal serotonin signaling in the synapse of sensory neurons and enterochromaffin (EC) cells. In conclusion, the results demonstrate the mechanism of interaction between Sch C and 5-HT3A receptor and reveal Sch C as a novel antagonist.

Modulation of the 5-HT3A receptor current by desacylbaldrinal.

The serotonin (5-hydroxytryptamine) type 3 receptor is an important target in the control of digestive dysfunction such as anorexia and bulimia, and 5-HT3 receptor antagonists are effective against eating disorder and the early-phase chemotherapy and radiotherapy evoked vomiting. Our previous research of Valeriana jatamansi revealed the presence of iridoids, which showed potent antitumor activities. Here, we explored the effects of 10π aromatic iridoid desacylbaldrinal isolated from V. jatamansi on the 5-HT3 receptor current. We performed whole cell recordings of 5-HT3A receptor currents in the presence of the compound. The result indicated that desacylbaldrinal inhibited the 5-HT-mediated 5-HT3A receptor current.

The Traditional Medicine Banhasasim-Tang Depolarizes Pacemaker Potentials of Cultured Interstitial Cells of Cajal through M3 Muscarinic and 5-HT3 Receptors in Murine Small Intestine.

BACKGROUND: Banhasasim-tang (BHSST) is a classic herbal formulation in traditional Chinese medicine widely used for gastrointestinal (GI) tract motility disorder. We investigated the effects of BHSST on the pacemaker potentials of cultured interstitial cells of Cajal (ICCs) in small intestine in vitro and its effects on GI motor functions in vivo. METHODS: We isolated ICCs from the small intestines and recorded pacemaker potentials in cultured ICCs with the whole-cell patch-clamp configuration in vitro. Intestinal transit rates (ITR%) were investigated in normal mice and GI motility dysfunction (GMD) mouse models in vivo. RESULTS: BHSST (20-50 mg/mL) depolarized pacemaker potentials and decreased their amplitudes in a concentration-dependent manner. Pretreatment with methoctramine (a muscarinic M2 receptor antagonist) did not inhibit BHSST-induced pacemaker potential depolarization. However, when we applied 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP; a muscarinic M3 receptor antagonist), BHSST-induced effects were blocked. Pretreatment with Y25130 (a 5-HT3 receptor antagonist) blocked BHSST-induced effects in ICCs. In addition, when we applied 4-DAMP and Y25130 together, BHSST-induced effects were completely blocked. Pretreatment with Ca2+-free solution or thapsigargin inhibited BHSST-induced effects. Moreover, BHSST blocked both the transient receptor potential melastatin (TRPM) 7 and voltage-sensitive calcium-activated chloride (anoctamin-1, ANO1) channels. In normal mice, ITR% values were significantly increased by BHSST in a dose-dependent manner. The ITR% of GMD mice was significantly reduced relative to those of normal mice, which were significantly reversed by BHSST in a dose-dependent manner. CONCLUSION: These results suggested that BHSST depolarizes the pacemaker potentials of ICCs in a dose-dependent manner through the M3 and 5-HT3 receptors via internal and external Ca2+-dependent and TRPM7- and ANO1-independent pathways in vitro. Moreover, BHSST increased ITR% in vivo in normal mice and GMD mouse models. Taken together, the results of this study showed that BHSST had the potential for development as a prokinetic agent in GI motility function.

Yokukansan-induced reduction of ethanol preference is associated with antagonism of 5-HT3 receptors.

BACKGROUND: We recently reported that alkaloids in Uncaria hook (a constituent of yokukansan) contribute to antagonism of 5-HT3 receptors. Many studies have reported that 5-HT3 receptor antagonists reduce alcohol preference. However, the effect of yokukansan on alcohol preference is not clear. PURPOSE: This study was performed to investigate the direct effect of yokukansan on alcohol preference and the effect of 5-HT3 receptors on the preference. STUDY DESIGN: We examined ethanol preference effected by yokukansan. Next, we analyzed the contribution of 5-HT3 receptors to the effect of yokukansan. METHODS: Ethanol preference was measured using the two-bottle preference test in mice fed with or without yokukansan diet. Next, the contribution of 5-HT3 receptors to ethanol preference was investigated using 5-HT3 receptor-deficient mice. RESULTS: Reduction of ethanol preference by yokukansan was not observed using 5-HT3 receptor deficient mice. CONCLUSION: Yokukansan contributes to reduced ethanol preference and antagonism of 5-HT3 receptors is associated with the effect.

Anti-inflammatory and antinociceptive activities of glucagon-like peptides: evaluation of their actions on serotonergic, nitrergic, and opioidergic systems.

RATIONALE: Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are gut derived hormones. GLP-1 and GLP-2 were shown to have pleiotropic effects in intestinal and pancreatic diseases. OBJECTIVE: We aimed to investigate the activities of GLP-1 and GLP-2 on nociception and inflammation in mice, involving their actions on serotonergic, nitrergic, and opioidergic systems. METHODS: Antinociceptive and anti-inflammatory activities of intraperitoneally injected GLPs were evaluated in hotplate latency test, formalin-induced behavioral, and paw edema tests. Ondansetron, a selective 5-HT3 receptor antagonist; L-NAME, a NOS inhibitor; and naloxone, an opioid antagonist were injected to determine the mechanisms of antinociception and anti-inflammation. We also measured blood glucose levels and performed rotarod test in order to evaluate whether the hypoglycemic effect of GLP compounds or alterations in locomotor activity may affect the latency in hotplate test and activity in formalin test. RESULTS: GLP-1 (0.2 mg/kg) and GLP-2 (0.05, 0.2 mg/kg) significantly increased pain threshold. GLP-1 (0.2 mg/kg) and GLP-2 (0.05, 0.1, 0.2 mg/kg) significantly decreased formalin-induced licking and shaking behaviors. GLP-1 or GLP-2 showed no significant inhibitory action on formalin-induced swelling in paws of mice. Antinociceptive actions of GLP-1 and GLP-2 were significantly decreased with ondansetron and naloxone, and paw shaking behavior significantly increased with naloxone. GLP-1 and GLP-2 did not impair rotarod performance, and did not cause a significant hypoglycemic effect in our normoglycemic mice after rotarod test. CONCLUSION: These finding indicated that the antinociceptive and anti-inflammatory effect of GLP-1 was related to opioidergic system. Antinociceptive effect of GLP-2 was partially related to 5-HT3 serotonergic or opioidergic system in hotplate test. However, the anti-inflammatory effect of GLP-2 was not directly related to 5-HT3, NO or opioids.

Yokukansan contains compounds that antagonize the 5-HT3 receptor.

BACKGROUND: We recently focused on alkaloids in Uncaria hook (a constituent of the Kampo medicine, yokukansan) and identified the pharmacological action of geissoschizine methyl ether on several G protein-coupled receptors. However, the functions of other identified alkaloids in Uncaria hook, including hirsutine, hirsuteine, rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine, are not clear. PURPOSE: To evaluate the effect of seven alkaloids in Uncaria hook (hirsutine, hirsuteine, rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine and geissoschizine methyl ether) on the hydroxytryptamine type-3 (5-HT3) receptor ion channel. STUDY DESIGN: We examined the effect of these alkaloids on the current of human 5-HT3 receptors expressed in Xenopus laevis oocytes. METHODS: The human 5-HT3A subunit alone for the 5-HT3A receptor, or 5-HT3A and 5-HT3B subunits for the 5-HT3AB receptor, were expressed in Xenopus laevis oocytes. The 5-HT current was measured with or without alkaloid application using a two-electrode voltage clamp. RESULTS: Each alkaloid, except for geissoschizine methyl ether, weakly inhibited the 5-HT-mediated 5-HT3A and/or 5-HT3AB receptor current, but co-application of these seven alkaloids inhibited the current strongly. CONCLUSION: Each alkaloid contributes to antagonism of the 5-HT3 receptor.

Efficacy and Safety of Serotonin Receptor Ligands in the Treatment of Irritable Bowel Syndrome: A Review.

BACKGROUND: Irritable bowel syndrome (IBS) is a chronic, recurrent bowel disorder with an unknown etiology, which is most likely multifactorial. Increased mucosal permeability, visceral hypersensitivity and activation status of intestinal mucosal immune cells cause changes in gastrointestinal (GI) motility, secretion and sensation observed in the course of IBS. Permanent, cumbersome symptoms, such as diarrhea, constipation and abdominal pain greatly lower the quality of life of IBS patients. On this basis, according to the Rome IV criteria, different forms of IBS can be distinguished. OBJECTIVE: This article focuses on the role of serotonin system in the pathophysiology of IBS as a potential therapeutic target. We shortly describe several molecules, associated with serotonin receptors, mainly 5-HT3 receptor antagonists and 5-HT4 receptor agonists, that are used in the treatment of motility disorders and visceral pain in IBS patients. We summarize the findings obtained in the clinical trials and elaborate on the safety of the serotonin ligands. Although the majority of serotonin receptor ligands relieve global symptoms, there are also some adverse effects, which can be dangerous for patients. RESULTS AND CONCLUSION: We postulate that currently, among all serotonin-targeting compounds, ramosetron is the best treatment option for IBS-D patients, due to its exceptional efficacy in both genders as well as good tolerability. Whereas, tegaserod is highly recommended for IBS-C sufferers. Nevertheless, numerous studies on the new serotonin receptor ligands are conducted to ensure the delivery of novel compounds with improved efficacy and safety profiles.

Blockade of 5-HT3 receptors with granisetron does not affect trigeminothalamic nociceptive transmission in rats: Implication for migraine.

One way to expand the existing range of anti-migraine drugs seems to be the search for pharmacological agents with anti-cephalalgic properties among medicines approved for clinical indications other than migraine. Numerous experimental and clinical data imply that selective serotonin 5-HT3 receptor antagonists can be considered as potential anti-migraine agents. Therefore, the objective of our work was to examine the impact of selective 5-HT3 receptor blockade with granisetron on migraine-related nociceptive transmission within the spinal trigeminal nucleus (STN) and the ventroposteromedial nucleus of the thalamus (VPM). Using an electrophysiological model of trigemino-durovascular nociception in anaesthetised male Wistar rats, we evaluated the effects of intravenous administration of granisetron on ongoing firing and dural electrical stimulation-evoked responses of the spinal trigeminal and thalamic cells. Granisetron did not substantially affect responses of the STN and VPM neurons to electrical stimulation of the dura mater as well as did not cause steady changes in ongoing firing of the spinal trigeminal cells. The results obtained argue against the use of 5-HT3 receptor antagonists for treating migraine. These data also lead to the conclusion that in the absence of sustained sensitisation of neurons along the trigemino-thalamo-cortical pathway the role of 5-HT3 receptor-dependent mechanisms in serotonergic modulation of trigeminovascular nociceptive transmission can hardly be considered crucial.

Hwangryunhaedok-tang induces the depolarization of pacemaker potentials through 5-HT3 and 5-HT4 receptors in cultured murine small intestine interstitial cells of Cajal.

AIM: To investigate the effects of a water extract of Hwangryunhaedok-tang (HHTE) on the pacemaker potentials of mouse interstitial cells of Cajal (ICCs). METHODS: We dissociated ICCs from small intestines and cultured. ICCs were immunologically identified using an anti-c-kit antibody. We used the whole-cell patch-clamp configuration to record the pacemaker potentials generated by cultured ICCs under the current clamp mode (I = 0). All experiments were performed at 30 °C-32 °C. RESULTS: HHTE dose-dependently depolarized ICC pacemaker potentials. Pretreatment with a 5-HT3 receptor antagonist (Y25130) or a 5-HT4 receptor antagonist (RS39604) blocked HHTE-induced pacemaker potential depolarizations, whereas pretreatment with a 5-HT7 receptor antagonist (SB269970) did not. Intracellular GDPßS inhibited HHTE-induced pacemaker potential depolarization and pretreatment with a Ca2+-free solution or thapsigargin abolished the pacemaker potentials. In the presence of a Ca2+-free solution or thapsigargin, HHTE did not depolarize ICC pacemaker potentials. In addition, HHTE-induced pacemaker potential depolarization was unaffected by a PKC inhibitor (calphostin C) or a Rho kinase inhibitor (Y27632). Of the four ingredients of HHT, Coptidis Rhizoma and Gardeniae Fructus more effectively inhibited pacemaker potential depolarization. CONCLUSION: These results suggest that HHTE dose-dependently depolarizes ICC pacemaker potentials through 5-HT3 and 5-HT4 receptors via external and internal Ca2+ regulation and via G protein-, PKC- and Rho kinase-independent pathways.

Prevention of gastrointestinal side-effects in paediatric oncology: what are the guidelines?

PURPOSE OF REVIEW: Gastrointestinal side-effects, particularly with regard to alimentary tract mucositis and chemotherapy-induced nausea and vomiting (CINV), continue to be frequent and debilitating symptomatic conditions among children and adolescents receiving cytotoxic cancer therapy. Further avenues of progress for mucositis and CINV prevention in paediatric oncology setting are warranted. RECENT FINDINGS: The current article reviews the major guidelines and literature published in 2016 pertaining to the prevention of mucositis and CINV. Considerable professional organizational efforts have been made to develop consensus-based or evidence-based guidelines that periodically update to define basic standards of mucositis and CINV prevention. There are a few published works in 2016 that may contribute to the emerging evidence on prevention of mucositis and CINV in the paediatric setting for future guideline updates. SUMMARY: The concomitant use of 5-HT3 receptor antagonist and dexamethasone are effective to prevent acute and delayed CINV in children who are to receive highly or moderately emetogenic chemotherapy. Optimal control of acute and delayed CINV can prevent anticipatory CINV. Oral care protocols would be beneficial to prevent mucositis in children across all cancer treatment modalities. Cryotherapy or low-level light therapy may be applied to cooperative children undergoing chemotherapy or haematological stem cell transplant conditioning regimens with a high rate of mucositis.

Dietary and pharmacological treatment of abdominal pain in IBS.

This review introduces the principles of visceral sensation and appraises the current approaches to management of visceral pain in functional GI diseases, principally IBS. These approaches include dietary measures including fibre supplementation, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet, and pharmacological approaches such as antispasmodics, peppermint oil, antidepressants (tricyclic agents, selective serotonin reuptake inhibitors), 5-HT3 receptor antagonists (alosetron, ondansetron, ramosetron), non-absorbed antibiotic (rifaximin), secretagogues (lubiprostone, linaclotide), µ-opioid receptor (OR) and κ-OR agonist, δ-OR antagonist (eluxadoline), histamine H1 receptor antagonist (ebastine), neurokinin-2 receptor antagonist (ibodutant) and GABAergic agents (gabapentin and pregabalin). Efficacy and safety are discussed based on pivotal trials or published systematic reviews and meta-analysis, expressing ORs or relative risks and their 95% CIs. Potential new approaches may be based on recent insights on mucosal expression of genes, and microRNA and epigenetic markers in human biopsies and in animal models of visceral hypersensitivity.The objectives of this review are to appraise the physiology and anatomy of gut sensation and the efficacy in the relief of visceral pain (typically in IBS) of several classes of therapies. These include fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and different classes of medications (box 1). Box 1Classes of pharmacological agents for visceral painAntidepressants (tricyclic agents, selective serotonin reuptake inhibitors)Peppermint oil5-HT3 receptor antagonists (alosetron, ondansetron, ramosetron)Non-absorbed antibiotic (rifaximin)Secretagogues (lubiprostone, linaclotide)µ-Opioid receptor (OR) and κ-OR agonist and δ-OR antagonist (eluxadoline)Histamine H1 receptor antagonist (ebastine)Neurokinin-2 receptor antagonist (ibodutant)GABAergic agents (gabapentin and pregabalin).

Neuropharmacological and neurochemical evaluation of N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n): a novel serotonergic 5-HT3 receptor antagonist for co-morbid antidepressant- and anxiolytic-like potential using traumatic brain injury model in rats.

BACKGROUND: Several preclinical studies have shown that serotonergic 5-HT3 receptor antagonists play an important role in the management of neuropsychiatric disorders, such as depression and anxiety. In the present study the compound "6n" (N-n-propyl-3-ethoxyquinoxaline-2-carboxamide), a novel 5-HT3 receptor antagonist with an optimal log P (2.52) and pA2 (7.6) value was screened for its neuro-pharmacological potential in chronic rodent models of depression and anxiety named traumatic brain injury (TBI). METHODS: In this model, a 1 cm midline scalp incision was made, and the muscles were retracted to expose the skull. A stainless steel disc (10 mm in diameter and 3 mm in depth) was placed centrally between the lambda and bregma regions. The injury was induced using the impact acceleration model of TBI. Specifically, a 400 g metal weight was dropped from a height of 1 m guided by a straight pipe, onto the metal disc placed over the rat's skull. RESULTS: The behavioral anomalies of the TBI rats were attenuated by the chronic treatment of compound 6n (1 and 2 mg/kg, p.o.; 14 days) as observed by the modified open field test (ambulation, rearing, and fecal pellet), sucrose consumption test (% sucrose consumption), elevated plus maze [% open arm entries [OAE] and % time spent in open arm (TSOA)], and marble burying test (numbers). In addition, 6n also increased the levels of neurotransmitters (norepinephrine and serotonin) and brain derived neurotrophic factor (BDNF) in TBI rats. CONCLUSIONS: The result suggests that compound 6n exhibited antidepressant- and anxiolytic-like effects in rodent models of depression and anxiety.

Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6g) on lipopolysaccharide-induced anxiety models in mice.

BACKGROUND: 5-HT3 receptor antagonists play a key role in the management of psychiatric disorders such as, depression and anxiety. They may act through modulation of serotonergic transmission. In the present study, a novel and potential 5-HT3 receptor antagonist, 6g (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone, which exhibited good log P (3.08) and pA2 (7.5) values was screened for its anxiolytic property in lipopolysaccharide (LPS) induced anxiety models. METHODS: LPS, an endotoxin, present in the cell wall of Gram negative bacteria was injected 0.83 mg/kg, i.p. as a single dose to induce anxiety-like symptoms in mice. Compound 6g (1 and 2 mg/kg, p.o.) and standard fluoxetine (FLX) (20 mg/kg, p.o.) were injected to treatment groups for 7 days and evaluated in various behavioral paradigms such as elevated plus maze (EPM), light and dark (L/D) test, and open field test (OFT). Their effects on serotonin levels in mice brain were also examined. RESULTS: The results showed that LPS induced anxiety-like symptoms in mice, as indicated by a significantly decreased percentage open arm entries and percentage time spent in open arms in EPM; decreased time spent in light area and number of transition between chambers in L/D test; decreased ambulation and rearing scores in OFT. Compound 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) reversed the LPS-induced behavioral changes and significantly affected all the behavioral parameters mentioned above. In addition 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) increased the levels of serotonin in mice brain. CONCLUSIONS: Compound 6g produced anxiolytic-like effects in various anxiety paradigms in LPS-treated mice as well as restored the decreased serotonin levels in mice brain.

Shuyu Capsules Relieve Premenstrual Syndrome Depression by Reducing 5-HT3AR and 5-HT3BR Expression in the Rat Brain.

The effects of the Shuyu capsule on 5-HT3AR and 5-HT3BR expression in a rat model of premenstrual syndrome (PMS) depression and on 5-HT3AR and 5-HT3BR expression and hippocampal neuron 5-HT3 channel current were investigated, to elucidate its mechanism of action against PMS depression. PMS depression model rats were divided into depression and Shuyu- and fluoxetine-treated groups, which were compared to control rats for frontal lobe and hippocampal 5-HT3AR and 5-HT3BR expression and behavior. The depressed model rats displayed symptoms of depression, which were reduced in treated and normal control rats. Frontal lobe and hippocampal 5-HT3AR and 5-HT3BR levels were significantly higher in the model versus the control group and were significantly lower in the Shuyu group. As compared to control rats, the 5-HT3R channel current in the model group was significantly higher; the 5-HT3R channel current in hippocampal neurons treated with serum from Shuyu group rats was significantly lower than that in those treated with model group serum. Thus, PMS depression may be related to 5-HT3AR and 5-HT3BR expression and increased 5-HT3 channel current. Shuyu capsules rectified abnormal 5-HT3AR and 5-HT3BR expression and 5-HT3 channel current changes in a rat model; this finding may provide insight into treating PMS depression.

Synthesis and Pharmacological Evaluation of [11C]Granisetron and [18F]Fluoropalonosetron as PET Probes for 5-HT3 Receptor Imaging.

Serotonin-gated ionotropic 5-HT3 receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT3 receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril) and palonosetron (Aloxi), belong to a family of drugs (the "setrons") that are well established for clinical use. To enable us to better understand the actions of these drugs in vivo, we report the synthesis of 8-fluoropalonosetron (15) that has a binding affinity (Ki = 0.26 ± 0.05 nM) similar to the parent drug (Ki = 0.21 ± 0.03 nM). We radiolabeled 15 by nucleophilic 18F-fluorination of an unsymmetrical diaryliodonium palonosetron precursor and achieved the radiosynthesis of 1-(methyl-11C)-N-granisetron ([11C]2) through N-alkylation with [11C]CH3I, respectively. Both compounds [18F]15 (chemical and radiochemical purity >95%, specific activity 41 GBq/µmol) and [11C]2 (chemical and radiochemical purity ≥99%, specific activity 170 GBq/µmol) were evaluated for their utility as positron emission tomography (PET) probes. Using mouse and rat brain slices, in vitro autoradiography with both [18F]15 and [11C]2 revealed a heterogeneous and displaceable binding in cortical and hippocampal regions that are known to express 5-HT3 receptors at significant levels. Subsequent PET experiments suggested that [18F]15 and [11C]2 are of limited utility for the PET imaging of brain 5-HT3 receptors in vivo.

Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice.

Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechanical allodynia, acetone and von Frey filament tests were used, respectively. Significant allodynia signs were observed three days after an oxaliplatin injection (6 mg/kg, i.p.). BVA (0.25, 1, and 2.5 mg/kg, s.c., ST36) or morphine (0.5, 2, and 5 mg/kg, i.p.) alone showed dose-dependent anti-allodynic effects. The combination of BVA and morphine at intermediate doses showed a greater and longer effect than either BVA or morphine alone at the highest dose. Intrathecal pretreatment with the opioidergic (naloxone, 20 µg) or 5-HT3 (MDL-72222, 15 µg) receptor antagonist, but not with α2 adrenergic (idazoxan, 10 µg) receptor antagonist, blocked this additive effect. Therefore, we suggest that the combination effect of BVA and morphine is mediated by spinal opioidergic and 5-HT3 receptors and this combination has a robust and enduring analgesic action against oxaliplatin-induced neuropathic pain.

Japanese Society of Clinical Oncology clinical practice guidelines 2010 for antiemesis in oncology: executive summary.

The purpose of this article is to disseminate the standard of antiemetic therapy for Japanese clinical oncologists. On the basis of the Appraisal of Guidelines for Research and Evaluation II instrument, which reflects evidence-based clinical practice guidelines, a working group of the Japanese Society of Clinical Oncology (JSCO) reviewed clinical practice guidelines for antiemesis and performed a systematic review of evidence-based domestic practice guidelines for antiemetic therapy in Japan. In addition, because health-insurance systems in Japan are different from those in other countries, a consensus was reached regarding standard treatments for chemotherapy that induce nausea and vomiting. Current evidence was collected by use of MEDLINE, from materials from meetings of the American Society of Clinical Oncology National Comprehensive Cancer Network, and from European Society of Medical Oncology/Multinational Association of Supportive Care in Cancer guidelines for antiemesis. Initially, 21 clinical questions (CQ) were selected on the basis of CQs from other guidelines. Patients treated with highly emetic agents should receive a serotonin (5-hydroxytryptamine; 5HT3) receptor antagonist, dexamethasone, and a neurokinin 1 receptor antagonist. For patients with moderate emetic risk, 5HT3 receptor antagonists and dexamethasone were recommended, whereas for those receiving chemotherapy with low emetic risk dexamethasone only is recommended. Patients receiving high-emetic-risk radiation therapy should also receive a 5HT3 receptor antagonist. In this paper the 2010 JSCO clinical practice guidelines for antiemesis are presented in English; they reveal high concordance of Japanese medical circumstances with other antiemetic guidelines that are similarly based on evidence.

Management of Postembolization Syndrome Following Hepatic Transarterial Chemoembolization for Primary or Metastatic Liver Cancer.

BACKGROUND: Transarterial chemoembolization (TACE) is an established treatment in managing liver primary neoplasms or liver metastases. Postembolization syndrome (PES) is a common adverse event defined as fever without associated sepsis, pain in the right upper quadrant, and nausea and/or vomiting. OBJECTIVE: This integrative review aims to identify effective management strategies for PES or one of its characterizing symptoms (fever, pain, and nausea and/or vomiting). METHODS: Searches of electronic databases MEDLINE, EMBASE, and CINAHL were conducted. Fifteen articles were identified for inclusion. Seven addressed all symptoms of PES, and 8 studies focused on individual symptoms of PES. RESULTS: Interventions identified are intra-arterial lidocaine, oral and intravenous analgesics, steroids, wrist-ankle acupuncture, antibiotics, and 5-HT3 receptor antagonists. Findings are explicated according to individual symptoms of PES. Intra-arterial lidocaine, steroids, and a 5-HT3 receptor antagonist are found to offer potential benefit in the management of PES symptoms. CONCLUSION: A number of interventions have shown potential benefit in the management of PES. A systemic approach using combination therapy is necessary to effectively manage characterizing symptoms. Further research is needed to determine the impact of primary disease site, TACE technique, and chemotherapeutic agent on PES. IMPLICATIONS FOR PRACTICE: Oncology nurses are uniquely placed to undertake thorough patient assessment after TACE and implement early intervention to effectively manage PES.

A novel 5HT3 antagonist 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide) prevents diabetes-induced depressive phenotypes in mice: Modulation of serotonergic system.

Despite the presence of a multitudinous pharmacotherapy, diabetes-induced depressive disorder remains undertreated. Evidence suggests that brain serotonergic deficits are associated with depressive-like behavior in diabetes and that 5HT3 receptor (5HT3R) antagonists have serotonergic facilitatory effects. This study examined the effects of a novel 5HT3R antagonist, 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide), in diabetes-induced depressive phenotypes. Experimentally, (1) to evaluate the effects of 4i, mice with 8-weeks of diabetes (induced by streptozotocin, 200mg/kg, i.p.) were treated with vehicle, 4i (0.5 and 1mg/kg/day, i.p.), fluoxetine (10mg/kg/day, i.p.) for 4-weeks and subjected to neurobehavioral assays, followed by biochemical estimation of serotonin levels in midbrain, prefrontal-cortex and cerebellum. (2) To evaluate the role of 5HT3R in the postulated effect of 4i, diabetic mice were given 4i (1mg/kg/day, i.p.) after 1h of 1-(m-chlorophenyl)-biguanide (mCPBG, a 5HT3R agonist, 10mg/kg/day, i.p.) treatment and subjected to the same protocol. The results showed that diabetic mice exhibited a significant behavioral deficit, including depression-like behavior in forced swim test, anxiety-like in open field test and sociability deficits in social interaction test, along with a significant decrease in serotonin level in these brain regions. 4i (1mg/kg), similar to fluoxetine, prevented these behavioral abnormalities and normalized brain serotonin levels. 4i (0.5mg/kg) ameliorated only diabetes-induced depressive-like behavior and serotonin deficits, but not anxiety-like effects. mCPBG blunted 4i-mediated behavioral response and increase in brain serotonin levels. Altogether, this study suggests that 4i prevents diabetes-induced depressive phenotypes in mice, which may involve antagonism of 5HT3Rs and increase in serotonin levels in discrete brain regions.