Emetic Response Research Articles

Non-pharmacological treatments for anticipatory nausea and vomiting during chemotherapy: a systematic review and meta-analysis of the Clinical Practice Guidelines for Antiemesis 2023.

Anticipatory chemotherapy-induced nausea and vomiting (CINV) is a conditioned response influenced by the severity and duration of previous emetic responses to chemotherapy. We aimed to evaluate the efficacy of non-pharmacologic interventions for anticipatory CINV among patients with cancer. We conducted a systematic search in databases, including PubMed, the Cochrane Library, CINAHL, and Ichushi-Web, from January 1, 1990, to December 31, 2020. Randomized controlled trials, non-randomized designs, observational studies, or case-control studies that utilized non-pharmacological therapies were included. The primary outcomes were anticipatory CINV, with an additional investigation into adverse events and the costs of therapies. The risk-of-bias for each study was assessed using the Cochrane risk-of-bias tool, and meta-analysis was performed using Revman 5.4 software. Of the 107 studies identified, six met the inclusion criteria. Three types of non-pharmacological treatments were identified: systematic desensitization (n = 2), hypnotherapy (n = 2), and yoga therapy (n = 2). Among them, systematic desensitization significantly improved anticipatory CINV as compared to that in the control group (nausea: risk ratio [RR] = 0.60, 95% confidence interval [CI] = 0.49-0.72, p < 0.00001; vomiting: RR = 0.54, 95% CI = 0.32-0.91, p = 0.02). However, heterogeneity in outcome measures precluded meta-analysis for hypnotherapy and yoga. Additionally, most selected studies had a high or unclear risk of bias, and adverse events were not consistently reported. Our findings suggest that systematic desensitization may effectively reduce anticipatory CINV. However, further research is warranted before implementation in clinical settings.

OLANZAPINE FOR NAUSEA AND VOMITING IN VARIOUS ETIOLOGIES : A REVIEW

Nausea is an unpleasant response followed by the risk of vomiting that results rapid forced ejection of gastric substance from the stomach upwards and out of the mouth. The Gastrointestinal tract, vestibular system, and thalamus are the sites that cause this event. Serotonin type 3 (5-HT3), Mu, neurokinin-1 (NK-1), kappa opioids, dopamine type 2 (D2) are CTZ receptors that cause emesis. 5-HT3 antagonists, antihistamines, and phenothiazines are common antiemetic agents. Olanzapine is an atypical antipsychotic second-generation medication with antiemetic properties. This article review used a classical method to identify studies related to the mechanism and efficacy of olanzapine as an antiemetic. The journal article related to olanzapine in nausea and vomiting that published on 2002 until 2022 for critical appraisal. The purpose of this literature review is to provide a review of antiemetics, especially olanzapine as a therapy option, as well as to evaluate the mechanism and efficacy of olanzapine. The activity of olanzapine with several receptors associated with nausea and vomiting suggests that it may have antiemetic activity. Olanzapine inhibits the 5-HT2C receptor, which is located near small intestine enterochromaffin cells and is required for the emetic response. In CINV therapy, research suggests combining olanzapine 10 mg with a 5-HT3 antagonist, NK-1 antagonist, dexamethasone. There is a lack of data in literature on the use of olanzapine in hyperemesis gravidarum. From the review we concluded that olanzapine can be considered for use as a therapy for the treatment of nausea and vomiting.

RF04 | PSUN295 Evolution of Monomeric Multi-Agonists of GLP-1 and NPY Receptors

Abstract Current treatments for type 2 diabetes (T2D) and obesity do not reliably achieve long-term weight-loss and up to 50% of patients experience nausea and vomiting. Thus, there is a critical need for obesity medications that provide glycemic control with enhanced hypophagic response without nausea/emesis. Based on rational design and in silico modelling of the glucagon-like peptide 1-receptor agonist (GLP1RA) exendin-4 (Ex4) and the neuropeptide Y2 receptor (Y2R) agonist peptide YY (PYY) 3-36, we have developed and screeened several new monomeric chimeric peptides that display dual agonism of the anorectic Y2R and the glucoregulatory GLP1R. In addition, we explored a third agonistic behavior at the neuropeptide Y1 receptor (Y1R), which potentially relates to pancreatic beta-cell protection. Our current lead, GEP44, binds the Y2R, Y1R, and GLP1R. We tested effects of daily injections of these chimeric peptides in adult Sprague-Dawley rats on food intake (FI), body weight (BW) changes, blood glucose levels and an indicator of nausea (kaolin intake). GEP44 produced profound reduction in FI (2-d average GEP44 at 20 nmol/kg FI -71%; Ex-4 20 nmol/kg FI -40%). Anorectic doses of GEP44 did not trigger a pica response assessed by kaolin consumption in treated rats, while in Ex-4 treated rats, kaolin consumption accounted for 28% of total daily solid intake, indicating a clear nausea response. In addition, we assayed for emetic response in the musk shrew, with little to no such emesis displayed (n=8) for GEP44 (1/8), but emesis noted across all animals tested for Ex4. During 11 d of treatment with GEP44, FI was consistently reduced resulting in a significantly stronger reduction of BW compared to Ex4 at the end of treatment (GEP44 -7.6%, Ex4 -3.7%, p&amp;lt;0.05). Furthermore, 5-day injections of GEP44 showed greater reduction of glucose levels than for Ex4 in diet induced obese rats receiving ip glucose. In conclusion, simultaneously targeting serial anorectic pathways with single molecule chimeric peptides can address multiple coexisting conditions to more efficaciously reduce FI, BW and blood glucose levels, devoid of side-effects to improve patient patient and quality of life. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Emetic Response to T-2 Toxin Correspond to Secretion of Glucagon-like Peptide-17-36 Amide and Glucose-Dependent Insulinotropic Polypeptide.

The T-2 toxin, a major secondary metabolite of Fusarium Gramineae, is considered a great risk to humans and animals due to its toxicity, such as inducing emesis. The mechanism of emesis is a complex signal involving an imbalance of hormones and neurotransmitters, as well as activity of visceral afferent neurons. The T-2 toxin has been proven to induce emesis and possess the capacity to elevate expressions of intestinal hormones glucagon-like peptide-17–36 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which are important emetic factors. In addition, the activation of calcium-sensitive receptor (CaSR) and transient receptor potential (TRP) channels are engaged in intestinal hormone release. However, it is unknown whether hormones GLP-1 and GIP mediate T-2 toxin-induced emetic response through activating CaSR and TRP channels. To further assess the mechanism of T-2 toxin-induced emesis, we studied the hypothesis that T-2 toxin-caused emetic response and intestinal hormones GLP-1 and GIP released in mink are associated with activating calcium transduction. Following oral gavage and intraperitoneal injection T-2 toxin, emetic responses were observed in a dose-dependent manner, which notably corresponded to the secretion of GLP-1 and GIP, and were suppressed by pretreatment with respective antagonist Exending9–39 and Pro3GIP. Additional research found that NPS-2143 (NPS) and ruthenium red (RR), respective antagonists of CaSR and TRP channels, dramatically inhibited both T-2 toxin-induced emesis response and the expression of plasma GLP-1 and GIP. According to these data, we observed that T-2 toxin-induced emetic response corresponds to secretion of GLP-1 and GIP via calcium transduction.

Glucose-Dependent Insulinotropic Polypeptide and Substance P Mediate Emetic Response Induction by Masked Trichothecene Deoxynivalenol-3-Glucoside through Ca2+ Signaling.

Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-occurs with DON as its glucosylated form and is another emerging food safety issue in recent years. However, the toxicity of D3G is not fully understood compared to DON, especially in emetic potency. The goals of this research were to (1) compare emetic effects to D3G by oral and intraperitoneal (IP) routes and relate emetic effects to brain-gut peptides glucose-dependent insulinotropic polypeptide (GIP) and substance P (SP) in mink; (2) determine the roles of calcium-sensing receptor (CaSR) and transient receptor potential (TRP) channel in D3G’s emetic effect. Both oral and IP exposure to D3G elicited marked emetic events. This emetic response corresponded to an elevation of GIP and SP. Blocking the GIP receptor (GIPR) diminished emetic response induction by GIP and D3G. The neurokinin 1 receptor (NK-1R) inhibitor Emend® restrained the induction of emesis by SP and D3G. Importantly, CaSR antagonist NPS-2143 or TRP channel antagonist ruthenium red dose-dependently inhibited both D3G-induced emesis and brain-gut peptides GIP and SP release; cotreatment with both antagonists additively suppressed both emetic and brain-gut peptide responses to D3G. To summarize, our findings demonstrate that activation of CaSR and TRP channels contributes to D3G-induced emesis by mediating brain-gut peptide exocytosis in mink.

Prodromal Physiologic Changes During Copper Sulfate‐Induced Nausea and Vomiting: Potential Use of Intestinal EMG Recordings as a Marker for Nausea

Although emetic responses are present during many disease states, there is no consensus regarding the physiologic changes that signal the onset of nausea. In this study, 10 adult felines (6 males and 4 females) were instrumented to chronically record, during the awake state, the electrocardiogram, diaphragm and abdominal muscle electromyographic (EMG) activity, and EMG activity from the stomach and duodenum before and after the gavage or intragastric infusion of saline or copper sulfate (CuSO4, doses ranging from 83 to 322 mg). Intragastric CuSO4 is a prototypical emetic stimulus that triggers emesis primarily by activating a gastrointestinal vagus nerve‐to‐brain pathway. CuSO4 infusion elicited a significant increase in heart rate, decrease in respiratory rate, and a disruption in gastric (baseline~6 CPM, cycles‐per‐minute) and intestinal (baseline~20 CPM) EMG activity several minutes prior to vomiting (see Fig. 1). The change in EMG activity was most consistent in the intestine. Administration of saline did not induce these physiologic changes. Increasing the dose of CuSO4 did not alter the physiologic changes induced by the treatment. In some animals, a second bout of vomiting occurred following the first episode, when prodromal changes of the intestinal EMG were less pronounced. It is postulated that the intestinal EMG activity was related to a retrograde movement of chyme from the intestine to the stomach. These findings suggest that monitoring of intestinal EMG activity may be the best indicator of the onset of nausea following treatments and in disease conditions associated with emesis.

Distribution of c‐Fos Labeling Elicited by Intragastric Copper Sulfate: Comparison with Labeling Induced by Galvanic Vestibular Stimulation

The neural pathways that produce nausea and emesis are poorly defined. Although it is widely postulated that a “final common pathway” is activated during emetic responses elicited by any stimulus, this hypothesis has not been adequately tested. In a prior study (Balaban et al., PLoS ONE 9(1): e86730, 2014) we mapped the distribution of Fos labeling in the feline brainstem elicited by galvanic vestibular stimulation (GVS) that evoked retching and other indicators of nausea. As a comparison, in the present study we mapped Fos labeling patterns induced by intragastric administration of copper sulfate (CuSO4), which produces emesis by activating vagal afferent fibers. Emetic responses slowly build‐up during GVS, but occur rapidly following CuSO4 administration. In 10 felines (6 male, 4 female), doses of CuSO4 ranging from 83 to 322 mg were administered through an intragastric catheter or gavage, and ~2 hours later animals were perfused with paraformaldehyde. The brain was sectioned and processed for Fos labeling as in our prior study (Balaban et al., PLoS ONE 9(1): e86730, 2014). Three additional animals served as controls and did not receive intragastric CuSO4. Some brainstem areas exhibited Fos labeling following either GVS or CuSO4 treatments, as shown in Fig. 1: the commissural, medial and lateral regions of nucleus tractus solitarii, lateral reticular nucleus, medullary lateral tegmental field, subtrigeminal nucleus, medullary raphe nuclei, parabrachial nucleus, and locus coeruleus. However, the labeling patterns also diverged: CuSO4 administration produced virtually no labeling in the vestibular nuclei (which was heavy following GVS), more labeling in nucleus tractus solitarii and the medullary raphe nuclei, and less labeling in the pontine raphe nuclei. These findings support the hypothesis that some brainstem areas mediate nausea and emesis induced by any stimulus, independent of how quickly the responses develop, but also suggest that unique pathways may be activated by particular emetic stimuli.

The trichothecene neosolaniol stimulates an emetic response through neuropeptide Y2 and serotonin 3 receptors in mink

Type A trichothecene neosolaniol (NEO) is considered a potential risk to human and animal health by the European Food Safety Authority (EFSA). To date, available data do not allow making conclusions about the toxicological properties of this toxin. Trichothecenes have been previously demonstrated to induce emetic responses in mink, and this response has been associated with neurotransmitter peptide YY (PYY) and serotonin (5-hydroxytryptamine, 5-HT). The goal of this study was to compare emetic effects of NEO administered by intraperitoneal and oral routes and relate these effects to PYY and 5-HT. The effective doses resulting in emetic events in 50% of the animals following intraperitoneal and oral exposure to NEO were 0.4 and 0.09 mg/kg bw, respectively. This emetic response corresponded to elevated PYY and 5-HT levels. Blocking the neuropeptide Y2 receptor diminished emesis induction by PYY and NEO. The 5-HT3 receptor inhibitor granisetron completely restrained the induction of emesis by 5-HT and NEO. To summarize, our findings demonstrate that PYY and 5-HT play important roles in the NEO-induced emetic response.

Vestibular migraine with isolated utricular or/and saccular hydrops in patients with motion sickness

Vestibular migraine is a newly recognised clinical entity, re­pre­sen­ted by presence of migraine headache and ver­ti­gi­nous symptoms. Vestibular migraine diagnosis is mainly cli­ni­cally based, but also a diagnosis by exclusion. Multiple stu­dies have been published lately, trying to iden­ti­fy speci­fi­cal fea­tures of vestibular migraine, in order to establish dif­­fe­­ren­­tia­­ting criteria for vestibular migraine and other ves­ti­bu­lar syndromes (especially Ménière’s disease). Some of these studies found an intimate relation between vestibular mi­graine and Ménière’s disease, vesti­bu­lar migraine and mo­tion sickness syndrome. We relate four clinical cases of ves­ti­bu­lar migraine associated with motion sickness syn­drome, all of these cases having some characteristics pre­vious­ly described as eloquent for the confirmation and dif­fe­ren­tia­ting diag­no­sis of vestibular migraine – abnormal response of ves­ti­bu­lar evoqued miogenic potentials (frequency tunning shift), intense emetic response at the caloric stimulation, asso­cia­tion with motion sickness syndrome.

Studies on the biological activities and emetic mechanism of staphylococcal enterotoxins

Staphylococcus aureus food poisoning was shown by Dack et al. in 1930 to be caused by staphylococcal enterotoxin (SE) produced by S. aureus, rather than by the bacterial infection. However, the emetic mechanism of SE has remained unclear. In this study, we analyzed the emetic activity of SE in several emetic animal models and tried to elucidate the mechanism of emesis. We established a small primate, common marmoset, as a novel emetic model for SE. We also analyzed the immunofluorescence analysis of the gastrointestinal tract of the common marmoset and found that SE binds to submucosal mast cells in the gastrointestinal tract and SE induces degranulation of the mast cells. Furthermore, we showed that SE induces histamine releases, which is inhibited by mast cell stabilizer. In addition, treatment of common marmosets with either mast cell stabilizer or histamine H1 receptor antagonists suppressed the emetic response induced by SE. These results indicate that orally administered SE binds to submucosal mast cells in the gastrointestinal tract and causes degranulation, resulting in the release of histamine, which in turn causes emesis.

Docking based screening and molecular dynamics simulations to identify potential selective PDE4B inhibitor

Inhibition of phosphodiesterase 4 (PDE4) is a promising therapeutic approach for the treatment of inflammatory pulmonary disorders, i.e. asthma and chronic obstructive pulmonary disease. However, the treatment with non-selective PDE4 inhibitors is associated with side effects such as nausea and vomiting. Among the subtypes of PDE4 inhibited by these inhibitors, PDE4B is expressed in immune, inflammatory and airway smooth muscle cells, whereas, PDE4D is expressed in the area postrema and nucleus of the solitary tract. Thus, PDE4D inhibition is responsible for the emetic response. In this regard, a selective PDE4B inhibitor is expected to be a potential drug candidate for the treatment of inflammatory pulmonary disorders. Therefore, a shared feature pharmacophore model was developed and used as a query for the virtual screening of Maybridge and SPECS databases. A number of filters were applied to ensure only compounds with drug-like properties were selected. Accordingly, nine compounds have been identified as final hits, where HTS04529 showed the highest affinity and selectivity for PDE4B over PDE4D in molecular docking. The docked complexes of HTS04529 with PDE4B and PDE4D were subjected to molecular dynamics simulations for 100ns to assess their binding stability. The results showed that HTS04529 was bound tightly to PDE4B and formed a more stable complex with it than with PDE4D.

Conditioned aversion in kea to cereal bait: A captive study using anthraquinone

The kea (Nestor notabilis, plural kea), an alpine parrot endemic to New Zealand’s South Island, is endangered by introduced mammalian predators. Aerially deployed 1080 (sodium fluoroacetate) toxin in cereal baits is an important tool in the control of mammalian pest species in New Zealand. Kea are omnivorous and forage on the ground, and thus are at direct risk of consuming toxic baits. This study examined the degree to which kea can develop an aversion to bait that mimicked the visual, textural, and olfactory nature of 1080 baits in two standard cereal bait types, Wanganui #7 and RS5. Treatment baits contained 2.7 % by weight anthraquinone (CAS 84-65-1), a secondary bird repellent that causes an emetic response through mild gut irritation. A sample of 11 captive kea were hand-offered Wanganui #7 baits, starting with untreated bait to obtain a baseline measure of consumption. Two days later the birds were hand-offered treated (repellent) baits in two sessions over four days. In subsequent sessions untreated baits were again offered to measure aversion. Of the 10 birds that consumed untreated bait during the initial session, all 10 consumed at least some treated bait and only one consumed untreated bait in the final session. The process was repeated with RS5 bait. Of the 9 kea that ate the treated RS5 bait, 4 subsequently consumed untreated bait but only one to a level that would have been fatal (LD50) with toxic bait. These results show that kea can learn to become averse to baits mimicking those used in aerial 1080 operations, and that this aversion response lasts at least through 6 interactions with baits (3 per day). This opens up the possibility of creating a learned aversion in wild kea populations, and mitigating their risk from aerial 1080 operations.

Preventive effects of naldemedine, peripherally acting μ-opioid receptor antagonist, on morphine-induced nausea and vomiting in ferrets

AimsNaldemedine is a peripherally acting μ-opioid receptor antagonists (PAMORAs) indicated for the treatment of opioid-induced constipation (OIC). We investigated the preventive effect of naldemedine on morphine-induced nausea and vomiting in ferrets and conducted a pharmacokinetic/pharmacodynamic (PK/PD) analysis. Main methodsThe antiemetic effect of naldemedine was evaluated as the frequency and time of retching (rhythmic abdominal contractile motion) and vomiting (throwing up vomit or similar reactions) caused by morphine in ferrets. After a single oral administration of naldemedine to ferrets, the plasma concentrations of naldemedine and morphine were measured by liquid chromatography–tandem mass spectrometry. Key findingsNaldemedine showed a potent and dose-dependent anti-emetic effects against morphine-induced emetic responses, for up to 6 h. The dose of naldemedine that produced half the maximal effect (ED50) value for anti-emetic effect of naldemedine in the morphine-treated ferrets was 0.033 mg/kg. The PK/PD analysis revealed that the antiemetic effect was related to the plasma naldemedine concentration, with a half maximal effective concentration that produces half the maximal effect (EC50) of 3.51 ng/mL. The plasma concentration producing an antiemetic effect was almost 200-fold lower than that inducing an anti-analgesic effect in rats. SignificanceNaldemedine showed potent inhibition of morphine-induced vomiting for up to 6 h after dosing. These data suggest that naldemedine possesses antiemetic properties and could be effective against opioid-induced nausea and vomiting (OINV).

Management of Chemotherapy-Induced Nausea and Vomiting (CINV): A Short Review on the Role of Netupitant-Palonosetron (NEPA).

IntroductionAntineoplastic drugs may induce several side effects, including chemotherapy-induced nausea and vomiting (CINV). Two neurotransmitters play a central role in mediating the emetic response: serotonin acting on the 5HT3 receptor and the substance P targeting the NK1 receptor. Indeed, a combination of a 5HT3 receptor antagonist (5HT3-RA) and a NK1 receptor antagonist (NK1-RA) together with dexamethasone has been shown to be very effective. In fact, this combination is actually widely used and recommended for CINV prophylaxis for highly emetogenic cisplatin-based adriamycin/cyclophosphamide (AC) and carboplatin-based regimens. NEPA (netupitant/palonosetron) is the only fixed combination antiemetic available and it is composed by the long-lasting second-generation 5HT3-RA palonosetron and the highly selective NK1-RA netupitant.AimThe aims of this short review were to analyze the role of NEPA in CINV prophylaxis and management taking in account the risk factors related to the patient and to the antineoplastic treatment.Evidence ReviewCINV development is not only correlated to the emetogenic potential of the antineoplastic drugs but is also very influenced by the patient characteristics and history, such as gender, age, alcohol intake, nausea during pregnancy and motion sickness. In pivotal and post-registration studies, NEPA has demonstrated to be effective and safe in both highly and moderately emetogenic chemotherapy.ConclusionA proper assessment of both chemotherapy- and patient-related risk factors is paramount to properly evaluate an appropriate prophylaxis of CINV and NEPA by simplifying the therapy, guarantees fully adherence to antiemetic guidelines, and consequently improves the control of CINV, especially in high risk patients.

Amisulpride: tackling postoperative nausea and vomiting not a nightmare any more

Vomiting and nausea remains concern in postoperative patients for anaesthesiologists and surgeons. Patients remain at risk for adverse medical consequences as wound dehiscence, dehydration, electrolyte derangement’s and gastric aspiration. This entity delays discharge and is one of the causes of unanticipated admission after ambulatory surgery. Presently dopamine (D2), serotonin (5-HT3), and histamine (H1) antagonists are widely used prophylactic agents, as is the corticosteroid dexamethasone, but the incidence of postoperative nausea and vomiting (PONV) is still appreciable. Safety concerns as QT interval prolongation has led to nearly phasing out of use of D2-antagonist Droperidol, a potent and most favoured formulation. With minimal studies and randomized studies to back up the efficacy of existing modalities viz 5HT-antagonist, promethazine, metoclopramide and dimenhydrinate for management of postoperative nausea and vomiting, need for evaluation, study and incorporation into formulary for management was always persisting. Amisulpride is an anti-psychotic agent, used routinely in &gt;50 countries worldwide is a potent but atypical D2-antagonist with minimal adverse profile mainly QT interval prolongation, extrapyramidal signs and symptoms, which had plagued out other members of same class. In addition to D2 antagonism this drug exhibits potent antagonist action against D3 receptors, implicated in the emetic response. In pre clinical studies and multiple randomized controlled multicenter studies the effectiveness and safety of low dose intra venous Amisulpride was established and approved as Barhemsys @Acacia Pharma by US Food and drug administration in February 2020. This drug will soon add to protocol-based management of PONV.

Type A Trichothecene Diacetoxyscirpenol-Induced Emesis Corresponds to Secretion of Peptide YY and Serotonin in Mink

The trichothecene mycotoxins contaminate cereal grains and have been related to alimentary toxicosis resulted in emetic response. This family of mycotoxins comprises type A to D groups of toxic sesquiterpene chemicals. Diacetoxyscirpenol (DAS), one of the most toxic type A trichothecenes, is considered to be a potential risk for human and animal health by the European Food Safety Authority. Other type A trichothecenes, T-2 toxin and HT-2 toxin, as well as type B trichothecene deoxynivalenol (DON), have been previously demonstrated to induce emetic response in the mink, and this response has been associated with the plasma elevation of neurotransmitters peptide YY (PYY) and serotonin (5-hydroxytryptamine, 5-HT). However, it is found that not all the type A and type B trichothecenes have the capacity to induce PYY and 5-HT. It is necessary to identify the roles of these two emetogenic mediators on DAS-induced emesis. The goal of this study was to determine the emetic effect of DAS and relate this effect to PYY and 5-HT, using a mink bioassay. Briefly, minks were fasted one day before experiment and given DAS by intraperitoneally and orally dosing on the experiment day. Then, emetic episodes were calculated and blood collection was employed for PYY and 5-HT test. DAS elicited robust emetic responses that corresponded to upraised PYY and 5-HT. Blocking the neuropeptide Y2 receptor (NPY2R) diminished emesis induction by PYY and DAS. The serotonin 3 receptor (5-HT3R) inhibitor granisetron totally restrained the induction of emesis by serotonin and DAS. In conclusion, our findings demonstrate that PYY and 5-HT have critical roles in DAS-induced emetic response.

Status of Brain Imaging in Gastroparesis

The pathophysiology of nausea and vomiting in gastroparesis is complicated and multifaceted involving the collaboration of both the peripheral and central nervous systems. Most treatment strategies and studies performed in gastroparesis have focused largely on the peripheral effects of this disease, while our understanding of the central nervous system mechanisms of nausea in this entity is still evolving. The ability to view the brain with different neuroimaging techniques has enabled significant advances in our understanding of the central emetic reflex response. However, not enough studies have been performed to further explore the brain–gut mechanisms involved in nausea and vomiting in patients with gastroparesis. The purpose of this review article is to assess the current status of brain imaging and summarize the theories about our present understanding on the central mechanisms involved in nausea and vomiting (N/V) in patients with gastroparesis. Gaining a better understanding of the complex brain circuits involved in the pathogenesis of gastroparesis will allow for the development of better antiemetic prophylactic and treatment strategies.

Roles of Substance P and NK1 Receptor in the Brainstem in the Development of Emesis

The emetic response is primarily a protective reflex occurring in a wide variety of vertebrates in response to the ingestion of toxic compounds. The role of the nuclei in the brainstem, including the area postrema, nucleus tractus solitarius, the dorsal motor nucleus of the vagus, and the central pattern generator for vomiting, as well as the involvement of the abdominal visceral innervation relevant to the emetic reflex, have all been discussed by many researchers. The introduction of serotonin 5-HT3-receptor antagonists into clinical practice allowed for a dramatic improvement in the management of vomiting. However, vomiting still remains a significant problem. The mechanism of the emetic response is even more complicated than was first thought. This review attempts to bring together some of the evidence suggesting the roles of substance P and its receptor, neurokinin NK1 receptor, in the brainstem nuclei in the development of emesis. Accordingly, NK1-receptor antagonists might represent novel drugs for the management of major types of emesis.

Alternative to Animal Use for Detecting Biologically Active Staphylococcal Enterotoxin Type A.

Staphylococcal enterotoxins (SEs) are a food safety concern. Existing methods for biologically active SE detection rely on the emetic response in live kittens or monkeys. This method suffers from low sensitivity, poor reproducibility, and causes ethical concerns regarding the use of experimental animals. The Lautenberg Chemical Safety Act encourages the development and adoption of alternatives to testing on animals for chemical toxicity methodologies. In this study, we utilized the superantigenic effect of SE type A (SEA) and used an ex vivo bioassay as an alternative to live animal testing. We found that interleukin-2 (IL-2) secreted by splenocyte can be utilized for quantifiable detection of SEA in food products. To avoid food matrix interference and attenuation of signal, we separated SEA from spiked food products by employing immunomagnetic beads that were coated with an anti-SEA antibody. This ex vivo method has achieved the detection of 1 ng mL−1 of SEA, which is 107 times more sensitive than the existing live animal testing methods. However, this ex vivo bioassay requires sacrificing of mice. To overcome this limitation, we established a cell based in vitro assay using CCRF-CEM, a human CD4+ T-cell line, for the quantitative detection of SEA. Incubation of SEA with CCRF-CEM human T-cells and Raji cells led to quantifiable and dose dependent secretion of IL-2. This novel cell-based assay is highly specific to biologically active SEA, compared with the related SE toxin subtypes B, D, and E or heat inactivated SEA, which produce no secretion of IL-2. This is the first demonstration of an alternative assay that completely eliminates the use of animals for quantitative detection of active SEA.

Further investigation of the effects of 5-hydroxytryptamine, 8-OH-DPAT and DOI to mediate contraction and relaxation responses in the intestine and emesis in Suncus murinus

5-HT receptors are implicated in many gastrointestinal disorders. However, the precise role of 5-HT in mediating GI responses in Suncus murnius is still unclear. Therefore in this study, the effects of 5-HT and its agonists were investigated in Suncus. The involvement of 5-HT2C receptors in mediating emesis was also investigated. The ability of 5-HT and its agonists/antagonists at 5-HT1A and 5-HT2 to modify GI motility was investigated in vitro and in vivo.WAY100635 (a 5-HT1A antagonist) inhibited the contraction response to 5-HT in the proximal segments without affecting the maximum response; whilst enhancing the contraction to 5-HT (>30.0nM) in the distal intestine. The selective 5-HT2A and 5-HT2B receptor antagonists MDL-100907 and RS-127445 attenuated 5-HT-induced contractions (<10.0µM) in the distal segments. RS-127445 also attenuated 5-HT-induced contractions in the central segments. The selective 5-HT2C receptor antagonist SB-242084, attenuated the responses to 5-HT (> 3.0nM) in the proximal and central but not the distal regions. 8-OH-DPAT-induced relaxation was resistant to the antagonism by 5-HT1A/7 antagonists. DOI in the presence of 5-HT1A/2A/2B/2C antagonists induced greater contraction responses (>1.0µM) in most tissues, whilst RS-127445, or SB-242084, reduced the responses to DOI (< 1.0µM) in some tissues. SB-242084 also suppressed emesis-induced by motion and intragastric CuSO4.In conclusion, within different regions of intestine, 5-HT2 receptors are differently involved in contraction and emetic responses and that 8-OH-DPAT induces relaxation via non-5-HT1A/7 receptors. Suncus could provide a model to investigate these diverse actions of 5-HT.