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Nausea is an uncomfortable sensation that accompanies many therapeutics, especially diabetes treatments involving glucagon-like peptide-1 receptor (GLP1R) agonists. Recent studies in mice have revealed that GLP1R-expressing neurons in the area postrema play critical roles in nausea. Here, we characterized a ligand-conjugated saporin that can efficiently ablate GLP1R + cells from humans, mice, and the Suncus murinus, a small animal model capable of emesis. This new tool provides a strategy to manipulate specific neural pathways in the area postrema in the Suncus murinus and may help elucidate roles of area postrema GLP1R + neurons in emesis during therapeutics involving GLP1R agonists., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: Gastric myoelectric signals have been the focus of extensive research; although it is unclear how general anesthesia affects these signals, and studies have often been conducted under general anesthesia. Here, we explore this issue directly by recording gastric myoelectric signals during awake and anesthetized states in the ferret and explore the contribution of behavioral movement to observed changes in signal power., Methods: Ferrets were surgically implanted with electrodes to record gastric myoelectric activity from the serosal surface of the stomach, and, following recovery, were tested in awake and isoflurane-anesthetized conditions. Video recordings were also analyzed during awake experiments to compare myoelectric activity during behavioral movement and rest., Key Results: A significant decrease in gastric myoelectric signal power was detected under isoflurane anesthesia compared to the awake condition. Moreover, a detailed analysis of the awake recordings indicates that behavioral movement is associated with increased signal power compared to rest., Conclusions & Inferences: These results suggest that both general anesthesia and behavioral movement can affect the signal power of gastric myoelectric recordings. In summary, caution should be taken in studying myoelectric data collected under anesthesia. Further, behavioral movement could have an important modulatory role on these signals, affecting their interpretation in clinical settings., (© 2024 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Vagus nerve stimulation (VNS) is a potential treatment option for gastrointestinal (GI) diseases. The present study aimed to understand the physiological effects of VNS on gastrointestinal (GI) function, which is crucial for developing more effective adaptive closed-loop VNS therapies for GI diseases. Electrogastrography (EGG), which measures gastric electrical activities (GEAs) as a proxy to quantify GI functions, was employed in our investigation. We introduced a recording schema that allowed us to simultaneously induce electrical VNS and record EGG. While this setup created a unique model for studying the effects of VNS on the GI function and provided an excellent testbed for designing advanced neuromodulation therapies, the resulting data was noisy, heterogeneous, and required specialized analysis tools. The current study aimed at formulating a systematic and interpretable approach to quantify the physiological effects of electrical VNS on GEAs in ferrets by using signal processing and machine learning techniques. Our analysis pipeline included pre-processing steps, feature extraction from both time and frequency domains, a voting algorithm for selecting features, and model training and validation. Our results indicated that the electrophysiological changes induced by VNS were optimally characterized by a distinct set of features for each classification scenario. Additionally, our findings demonstrated that the process of feature selection enhanced classification performance and facilitated representation learning., Competing Interests: No authors have competing interests., (Copyright: © 2023 Zeydabadinezhad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Functional and motility-related gastrointestinal (GI) disorders affect nearly 40% percent of the population. Disturbances of GI myoelectric activity have been proposed to play a significant role in these disorders. A significant barrier to usage of these signals in diagnosis and treatment is the lack of consistent relationships between GI myoelectric features and function. A potential cause of this issue is the use of arbitrary classification criteria, such as percentage of power in tachygastric and bradygastric frequency bands. Here we applied automatic feature extraction using a deep neural network architecture on GI myoelectric signals from free-moving ferrets. For each animal, we recorded during baseline control and feeding conditions lasting for 1 h. Data were trained on a 1-dimensional residual convolutional network, followed by a fully connected layer, with a decision based on a sigmoidal output. For this 2-class problem, accuracy was 90%, sensitivity (feeding detection) was 90%, and specificity (baseline detection) was 89%. By comparison, approaches using hand-crafted features (e.g., SVM, random forest, and logistic regression) produced an accuracy from 54% to 82%, sensitivity from 46% to 84% and specificity from 66% to 80%. These results suggest that automatic feature extraction and deep neural networks could be useful to assess GI function for comparing baseline to an active functional GI state, such as feeding. In future testing, the current approach could be applied to determine normal and disease-related GI myoelectric patterns to diagnosis and assess patients with GI disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Elkhadrawi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Nausea is a common disease symptom, yet there is no consensus regarding its physiological markers. In contrast, the process of vomiting is well documented as sequential muscular contractions of the diaphragm and abdominal muscles and esophageal shortening. Nausea, like other self-reported perceptions, is difficult to distinguish in preclinical models, but based on human experience emesis is usually preceded by nausea. Here we focused on measuring gastrointestinal and cardiorespiratory changes prior to emesis to provide additional insights into markers for nausea. Felines were instrumented to chronically record heart rate, respiration, and electromyographic (EMG) activity from the stomach and duodenum before and after intragastric delivery of saline or copper sulfate (CuSO 4 , from 83 to 322 mg). CuSO 4 is a prototypical emetic test agent that triggers vomiting primarily by action on GI vagal afferent fibers when administered intragastrically. CuSO 4 infusion elicited a significant increase in heart rate, decrease in respiratory rate, and a disruption of gastric and intestinal EMG activity several minutes prior to emesis. The change in EMG activity was most consistent in the duodenum. Administration of the same volume of saline did not induce these effects. Increasing the dose of CuSO 4 did not alter the physiologic changes induced by the treatment. It is postulated that the intestinal EMG activity was related to the retrograde movement of chyme from the intestine to the stomach demonstrated to occur prior to emesis by other investigators. These findings suggest that monitoring of intestinal EMG activity, perhaps in combination with heart rate, may provide the best indicator of the onset of nausea following treatments and in disease conditions, including GI disease, associated with emesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Murphey, Shulgach, Amin, Douglas, Bielanin, Sampson, Horn and Yates.)

Dysfunction and diseases of the gastrointestinal (GI) tract are a major driver of medical care. The vagus nerve innervates and controls multiple organs of the GI tract and vagus nerve stimulation (VNS) could provide a means for affecting GI function and treating disease. However, the vagus nerve also innervates many other organs throughout the body, and off-target effects of VNS could cause major side effects such as changes in blood pressure. In this study, we aimed to achieve selective stimulation of populations of vagal afferents using a multi-contact cuff electrode wrapped around the abdominal trunks of the vagus nerve. Four-contact nerve cuff electrodes were implanted around the dorsal (N = 3) or ventral (N = 3) abdominal vagus nerve in six ferrets, and the response to stimulation was measured via a 32-channel microelectrode array (MEA) inserted into the left or right nodose ganglion. Selectivity was characterized by the ability to evoke responses in MEA channels through one bipolar pair of cuff contacts but not through the other bipolar pair. We demonstrated that it was possible to selectively activate subpopulations of vagal neurons using abdominal VNS. Additionally, we quantified the conduction velocity of evoked responses to determine what types of nerve fibers (i.e., Aδ vs. C) responded to stimulation. We also quantified the spatial organization of evoked responses in the nodose MEA to determine if there is somatotopic organization of the neurons in that ganglion. Finally, we demonstrated in a separate set of three ferrets that stimulation of the abdominal vagus via a four-contact cuff could selectively alter gastric myoelectric activity, suggesting that abdominal VNS can potentially be used to control GI function.

Objective. Electrical vagus nerve stimulation (VNS) has the potential to treat a wide variety of diseases by modulating afferent and efferent communication to the heart, lungs, esophagus, stomach, and intestines. Although distal vagal nerve branches, close to end organs, could provide a selective therapeutic approach, these locations are often surgically inaccessible. In contrast, the cervical vagus nerve has been targeted for decades using surgically implantable helix electrodes to treat epileptic seizures and depression; however, to date, clinical implementation of VNS has relied on an electrode with contacts that fully wrap around the nerve, producing non-selective activation of the entire nerve. Here we demonstrate selective cervical VNS using cuff electrodes with multiple contacts around the nerve circumference to target different functional pathways. Approach. These flexible probes were adjusted to the diameter of the nerve using an adhesive hydrogel wrap to create a robust electrode interface. Our approach was verified in a rat model by demonstrating that cervical VNS produces neural activity in the abdominal vagus nerve while limiting effects on the cardiovascular system (i.e. changes in heart rate or blood pressure). Main results. This study demonstrates the potential for selective cervical VNS as a therapeutic approach for modulating distal nerve branches while reducing off target effects. Significance. This methodology could potentially be refined to treat gastrointestinal, metabolic, inflammatory, cardiovascular, and respiratory diseases amenable to vagal neuromodulatory control., (© 2021 IOP Publishing Ltd.)

Aim: To develop a conjugate of vitamin B12 bound to the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex4) that shows reduced penetrance into the central nervous system while maintaining peripheral glucoregulatory function., Methods: We evaluated whether a vitamin B12 conjugate of Ex4 (B12-Ex4) improves glucose tolerance without inducing anorexia in Goto-Kakizaki (GK) rats, a lean type 2 diabetes model of an understudied but medically compromised population of patients requiring the glucoregulatory effects of GLP-1R agonists without anorexia. We also utilized the musk shrew (Suncus murinus), a mammalian model capable of emesis, to test B12-Ex4 on glycaemic profile, feeding and emesis., Results: In both models, native Ex4 and B12-Ex4 equivalently blunted the rise in blood glucose levels during a glucose tolerance test. In both GK rats and shrews, acute Ex4 administration decreased food intake, leading to weight loss; by contrast, equimolar administration of B12-Ex4 had no effect on feeding and body weight. There was a near absence of emesis in shrews given systemic B12-Ex4, in contrast to reliable emesis produced by Ex4. When administered centrally, both B12-Ex4 and Ex4 induced similar potency of emesis, suggesting that brain penetrance of B12-Ex4 is required for induction of emesis., Conclusions: These findings highlight the potential therapeutic value of B12-Ex4 as a novel treatment for type 2 diabetes devoid of weight loss and with reduced adverse effects and better tolerance, but similar glucoregulation to current GLP-1R agonists., (© 2020 John Wiley & Sons Ltd.)

Growth differentiation factor 15 (GDF15) is a cytokine that reduces food intake through activation of hindbrain GFRAL-RET receptors and has become a keen target of interest for anti-obesity therapies. Elevated endogenous GDF15 is associated with energy balance disturbances, cancer progression, chemotherapy-induced anorexia, and morning sickness. We hypothesized that GDF15 causes emesis and that its anorectic effects are related to this function. Here, we examined feeding and emesis and/or emetic-like behaviors in three different mammalian laboratory species to help elucidate the role of GDF15 in these behaviors. Data show that GDF15 causes emesis in Suncus murinus (musk shrews) and induces behaviors indicative of nausea/malaise (e.g., anorexia and pica) in non-emetic species, including mice and lean or obese rats. We also present data in mice suggesting that GDF15 contributes to chemotherapy-induced malaise. Together, these results indicate that GDF15 triggers anorexia through the induction of nausea and/or by engaging emetic neurocircuitry., Competing Interests: Declaration of Interests B.C.D. receives research funding from Eli Lilly & Co. and Pfizer, Inc. and provided remunerated consultancy services for cachexia-related projects for Pfizer, Inc., not supporting these studies. R.P.D. is a scientific advisory board member and received funds from Xeragenx LLC (St. Louis, NY) and Balchem, New Hampton, New York that were not used in support of these studies. M.R.H. receives research funding from Zealand Pharma, Novo Nordisk, Eli Lilly & Co., and Boehringer Ingelheim that was not used in support of these studies. H.J.G. is a consultant and advisory board member for Novo Nordisk and receives research support from Pfizer, Inc. that was not used to support these studies. T.B., M.R.H., B.C.D., and R.P.D. are co-inventors and owners of a patent for a proprietary compound related to the GDF15-GFRAL system (serial #: 62/801,391). No other competing interests are declared., (Copyright © 2019. Published by Elsevier Inc.)

Although electrogastrography (EGG) could be a critical tool in the diagnosis of patients with gastrointestinal (GI) disease, it remains under-utilized. The lack of spatial and temporal resolution using current EGG methods presents a significant roadblock to more widespread usage. Human and preclinical studies have shown that GI myoelectric electrodes can record signals containing significantly more information than can be derived from abdominal surface electrodes. The current study sought to assess the efficacy of multi-electrode arrays, surgically implanted on the serosal surface of the GI tract, from gastric fundus-to-duodenum, in recording myoelectric signals. It also examines the potential for machine learning algorithms to predict functional states, such as retching and emesis, from GI signal features. Studies were performed using ferrets, a gold standard model for emesis testing. Our results include simultaneous recordings from up to six GI recording sites in both anesthetized and chronically implanted free-moving ferrets. Testing conditions to produce different gastric states included gastric distension, intragastric infusion of emetine (a prototypical emetic agent), and feeding. Despite the observed variability in GI signals, machine learning algorithms, including k-nearest neighbors and support vector machines, were able to detect the state of the stomach with high overall accuracy (>75%). The present study is the first demonstration of machine learning algorithms to detect the physiological state of the stomach and onset of retching, which could provide a methodology to diagnose GI diseases and symptoms such as nausea and vomiting., Competing Interests: BM, JO, LW, GC are employees of Micro-Leads Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Autonomic nerves are attractive targets for medical therapies using electroceutical devices because of the potential for selective control and few side effects. These devices use novel materials, electrode configurations, stimulation patterns, and closed-loop control to treat heart failure, hypertension, gastrointestinal and bladder diseases, obesity/diabetes, and inflammatory disorders. Critical to progress is a mechanistic understanding of multi-level controls of target organs, disease adaptation, and impact of neuromodulation to restore organ function.

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-HT 2C receptors in mediating emesis was also investigated. The ability of 5-HT and its agonists/antagonists at 5-HT 1A and 5-HT 2 to modify GI motility was investigated in vitro and in vivo. WAY100635 (a 5-HT 1A 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-HT 2A and 5-HT 2B 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-HT 2C 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-HT 1A/7 antagonists. DOI in the presence of 5-HT 1A/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 CuSO 4 . In conclusion, within different regions of intestine, 5-HT 2 receptors are differently involved in contraction and emetic responses and that 8-OH-DPAT induces relaxation via non-5-HT 1A/7 receptors. Suncus could provide a model to investigate these diverse actions of 5-HT., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Several cancer chemotherapies cause nausea and vomiting, which can be dose-limiting. Musk shrews are used as preclinical models for chemotherapy-induced emesis and for antiemetic effectiveness. Unlike rats and mice, shrews possess a vomiting reflex and demonstrate an emetic profile similar to humans, including acute and delayed phases. As with most animals, dosing of shrews is based on body weight, while translation of such doses to clinically equivalent exposure requires doses based on body surface area. In the current study body surface area in musk shrews was directly assessed to determine the Meeh constant (K m ) conversion factor (female = 9.97, male = 9.10), allowing estimation of body surface area based on body weight. These parameters can be used to determine dosing strategies for shrew studies that model human drug exposures, particularly for investigating the emetic liability of cancer chemotherapeutic agents.

Novel clinical treatments to target peripheral nerves are being developed which primarily use electrical current. Recently, infrared (IR) light was shown to inhibit peripheral nerves with high spatial and temporal specificity. Here, for the first time, we demonstrate that IR can selectively and reversibly inhibit small-diameter axons at lower radiant exposures than large-diameter axons. We provide a mathematical rationale, and then demonstrate it experimentally in individual axons of identified neurons in the marine mollusk Aplysia californica, and in axons within the vagus nerve of a mammal, the musk shrew Suncus murinus. The ability to selectively, rapidly, and reversibly control small-diameter sensory fibers may have many applications, both for the analysis of physiology, and for treating diseases of the peripheral nervous system, such as chronic nausea, vomiting, pain, and hypertension. Moreover, the mathematical analysis of how IR affects the nerve could apply to other techniques for controlling peripheral nerve signaling.

The incidence of postoperative nausea and vomiting (PONV) can be as high as 80% in patients with risk factors (e.g., females, history of motion sickness). PONV delays postoperative recovery and costs several hundred million dollars annually. Cell-based assays show that halogenated ethers (e.g., isoflurane) activate 5-HT 3 receptors, which are found on gastrointestinal vagal afferents and in the hindbrain - key pathways for producing nausea and vomiting. This project evaluated the role of the vagus and activation of the hindbrain in isoflurane-induced emesis in musk shrews, a small animal model with a vomiting reflex, which is lacking in rats and mice. Sham-operated and abdominal vagotomized shrews were exposed to 1 to 3% isoflurane to determine effects on emesis; vagotomy was confirmed by lack of vagal transport of the neuronal tracer Fluoro-Gold. In an additional study, shrews were exposed to isoflurane and hindbrain c-Fos was measured at 90min after exposure using immunohistochemistry. There were no statistically significant effects of vagotomy on isoflurane-induced emesis compared to sham-operated controls. Isoflurane exposure produced a significant increase in c-Fos-positive cells in the nucleus of the solitary tract and vestibular nuclei but not in the area postrema or dorsal motor nucleus. These results indicate that the abdominal vagus plays no role in isoflurane-induced emesis and suggest that isoflurane activates emesis by action on the hindbrain, as shown by c-Fos labeling. Ultimately, knowledge of the mechanisms of inhalational anesthesia-induced PONV could lead to more targeted therapies to control PONV., Competing Interests: Conflict of interests The authors declare no conflicts of interest., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Neurophysiology requires an extensive workflow of information analysis routines, which often includes incompatible proprietary software, introducing limitations based on financial costs, transfer of data between platforms, and the ability to share. An ecosystem of free open-source software exists to fill these gaps, including thousands of analysis and plotting packages written in Python and R, which can be implemented in a sharable and reproducible format, such as the Jupyter electronic notebook. This tool chain can largely replace current routines by importing data, producing analyses, and generating publication-quality graphics. An electronic notebook like Jupyter allows these analyses, along with documentation of procedures, to display locally or remotely in an internet browser, which can be saved as an HTML, PDF, or other file format for sharing with team members and the scientific community. The present report illustrates these methods using data from electrophysiological recordings of the musk shrew vagus-a model system to investigate gut-brain communication, for example, in cancer chemotherapy-induced emesis. We show methods for spike sorting (including statistical validation), spike train analysis, and analysis of compound action potentials in notebooks. Raw data and code are available from notebooks in data supplements or from an executable online version, which replicates all analyses without installing software-an implementation of reproducible research. This demonstrates the promise of combining disparate analyses into one platform, along with the ease of sharing this work. In an age of diverse, high-throughput computational workflows, this methodology can increase efficiency, transparency, and the collaborative potential of neurophysiological research., (Copyright © 2016 the American Physiological Society.)

Background: Gastric electrical stimulation (GES) is implicated as a potential therapy for difficult-to-treat nausea and vomiting; however, there is a lack of insight into the mechanisms responsible for these effects. This study tested the relationship between acute GES and emesis in musk shrews, an established emetic model system., Methods: Urethane-anesthetized shrews were used to record emetic responses (monitoring intra-tracheal pressure and esophageal contractions), respiration rate, heart rate variability, blood pressure, and gastrointestinal electromyograms. We investigated the effects of acute GES pulse duration (0.3, 1, 5, and 10 ms), current amplitude (0.5, 1, and 2 mA), pulse frequency (8, 15, 30, and 60 Hz), and electrode placement (antrum, body, and fundus) on emesis induced by gastric stretch, using a balloon., Key Results: There were four outcomes: (i) GES did not modify the effects of gastric stretch-induced emesis; (ii) GES produced emesis, depending on the stimulation parameters, but was less effective than gastric stretch; (iii) other physiological changes were closely associated with emesis and could be related to a sub-threshold activation of the emetic system, including suppression of breathing and rise in blood pressure; and (iv) a control experiment showed that 8-OH-DPAT, a reported 5-HT1A receptor agonist that acts centrally as an antiemetic, blocked gastric stretch-induced emesis., Conclusions and Inferences: These results do not support an antiemetic effect of acute GES on gastric distension-induced emesis within the range of conditions tested, but further evaluation should focus on a broader range of emetic stimuli and GES stimulation parameters., (© 2016 John Wiley & Sons Ltd.)

Purpose: Nausea is a common and potentially serious effect of cytotoxic chemotherapy for recurrent ovarian cancer and may function as a sentinel symptom reflecting adverse effects on the gut-brain axis (GBA) more generally, but research is scant. As a first exploratory test of this GBA hypothesis, we compared women reporting nausea to women not reporting nausea with regard to the severity of other commonly reported symptoms in this patient population., Methods: A secondary analysis of data systematically collected from women in active chemotherapy treatment for recurrent ovarian cancer (n = 158) was conducted. The Symptom Representation Questionnaire (SRQ) provided severity ratings for 22 common symptoms related to cancer and chemotherapy. Independent sample t tests and regression analyses were used to compare women with and without nausea with regard to their experience of other symptoms., Results: Nausea was reported by 89 (56.2 %) women. Symptoms that were significantly associated with nausea in bivariate and regression analyses included abdominal bloating, bowel disturbances, dizziness, depression, drowsiness, fatigue, headache, lack of appetite, memory problems, mood swings, shortness of breath, pain, sleep disturbance, urinary problems, vomiting, and weight loss. Symptoms that were not associated with nausea included hair loss, numbness and tingling, sexuality concerns, and weight gain., Conclusions: Nausea experienced during chemotherapy for recurrent ovarian cancer may be an indicator of broader effects on the gut-brain axis. A better understanding of the mechanisms underlying these effects could lead to the development of novel supportive therapies to increase the tolerability and effectiveness of cancer treatment.

Nausea and vomiting are among the most basic of human experiences and unfortunately accompany a wide variety of clinical treatments as side effects. Despite decades of research, the neural mechanisms of nausea and vomiting (emesis) remain elusive. TRPV1 represents a possibly overlooked and understudied pharmacological target with anti-emetic potential.

Purpose: Cisplatin induces nausea and emesis, even with antiemetic supportive care. To assess platinum exposure, which could activate nausea and emesis, we quantitated platinum in the brain and various organs, and hindbrain and spinal cord substance P, a key neuropeptide for the neuronal signaling of nausea and emesis., Methods: Musk shrews, a model species for nausea and emesis research, were dosed intraperitoneally with 20 mg/kg cisplatin and euthanized at up to 72 h after injection. Concentrations of platinum were quantitated in plasma ultrafiltrate, plasma, lung, kidney, combined forebrain and midbrain, hindbrain, and spinal cord by flameless atomic absorption spectrometry. Hindbrains and spinal cords were analyzed for substance P by immunohistochemistry after injection of 20 or 30 mg/kg., Results: Plasma ultrafilterable platinum concentrations decreased rapidly till 60 min after dosing and then more slowly by 24 h. The concentrations of total platinum in both the fore- and midbrain and the hindbrain were similar at all time points and were at least 20-fold lower than plasma total platinum concentrations. There were no significant changes in substance P immunoreactivity after cisplatin dosing. Histology revealed damage to the renal cortex by 72 h after injection of cisplatin., Conclusions: This is the first study to examine platinum concentrations in musk shrews after administration of cisplatin and delineate substance P immunohistochemical staining in the hindbrain and spinal cord of this species. The platinum concentrations detected in the brain could potentially contribute to the neurological side effects of cisplatin, such as nausea and emesis.

Nausea and vomiting are ubiquitous as drug side effects and symptoms of disease; however, the systems that determine these responses are arguably designed for protection against food poisoning occurring at the level of the gastrointestinal (GI) tract. This basic biological pathway using GI vagal afferent communication to the brain is not well understood. Part of this lack of insight appears to be related to current experimental approaches, such as the use of experimental drugs, including systemic chemotherapy and brain penetrant agents, which activate parts of the nausea and vomiting system in potentially unnatural ways. Directly related to this issue is our ability to understand the link between nausea and vomiting, which are sometimes argued to be completely separate processes, with nausea as an unmeasurable response in animal models. An argument is made that nausea and emesis are the efferent limbs of a unified sensory input from the GI tract that is likely to be impossible to understand without more specific animal electrophysiological experimentation of vagal afferent signaling. The current paper provides a review on the use of animal models and approaches to defining the biological systems for nausea and emesis and presents a potentially testable theory on how these systems work in combination.

Signals from the vestibular system, area postrema, and forebrain elicit nausea and vomiting, but gastrointestinal (GI) vagal afferent input arguably plays the most prominent role in defense against food poisoning. It is difficult to determine the contribution of GI vagal afferent input on emesis because various agents (e.g., chemotherapy) often act on multiple sensory pathways. Intragastric copper sulfate (CuSO4) potentially provides a specific vagal emetic stimulus, but its actions are not well defined in musk shrews (Suncus murinus), a primary small animal model used to study emesis. The aims of the current study were 1) to investigate the effects of subdiaphragmatic vagotomy on CuSO4-induced emesis and 2) to conduct preliminary transneuronal tracing of the GI-brain pathways in musk shrews. Vagotomy failed to inhibit the number of emetic episodes produced by optimal emetic doses of CuSO4 (60 and 120 mg/kg ig), but the effects of lower doses were dependent on an intact vagus (20 and 40 mg/kg). Vagotomy also failed to affect emesis produced by motion (1 Hz, 10 min) or nicotine administration (5 mg/kg sc). Anterograde transport of the H129 strain of herpes simplex virus-1 from the ventral stomach wall identified the following brain regions as receiving inputs from vagal afferents: the nucleus of the solitary tract, area postrema, and lateral parabrachial nucleus. These data indicate that the contribution of vagal pathways to intragastric CuSO4-induced emesis is dose dependent in musk shrews. Furthermore, the current neural tracing data suggest brain stem anatomical circuits that are activated by GI signaling in the musk shrew.

Susceptibility to motion sickness is a predictor of postoperative nausea and vomiting, and studies in humans suggest that genetic factors determine sensitivity to motion sickness. The aim of the current study was to determine if a preclinical model could be selectively bred for motion-induced emesis and to assess a potential relationship to anesthesia-induced emesis. Musk shrews were tested for motion-induced emesis using a shaker plate (10min, 1Hz, and 4cm of lateral displacement). Animals were rank ordered for motion-induced emesis and selectively bred to produce high and low response strains. Shrews were also tested with nicotine (5mg/kg, sc), copper sulfate (CuSO4; 120mg/kg, ig), and isoflurane anesthesia (10min; 3%) to measure responses to a panel of emetic stimuli. High response strain shrews demonstrated significantly more emetic episodes to motion exposure compared to low response strain animals in the F1 and F2 generations. In F2 animals, there were no significant differences in total emetic responses or emetic latency between strains after nicotine injection or CuSO4 gavage. However, isoflurane exposure stimulated more emesis in F1 and F2 high versus low strain animals, which suggests a relationship between vestibular- and inhalational anesthesia-induced emesis. Overall, these results indicate genetic determinants of motion sickness in a preclinical model and a potential common mechanism for motion sickness and inhalational anesthesia-induced emesis. Future work may include genetic mapping of potential "emetic sensitivity genes" to develop novel therapies or diagnostics for patients with high risk of nausea and vomiting., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Clinical research shows that postoperative nausea and vomiting (PONV) is caused primarily by the use of inhalational anesthesia and opioid analgesics. PONV is also increased by several risk predictors, including a young age, female sex, lack of smoking, and a history of motion sickness. Genetic studies are beginning to shed light on the variability in patient experiences of PONV by assessing polymorphisms of gene targets known to play roles in emesis (serotonin type 3, 5-HT3; opioid; muscarinic; and dopamine type 2, D2, receptors) and the metabolism of antiemetic drugs (e.g., ondansetron). Significant numbers of clinical trials have produced valuable information on pharmacological targets important for controlling PONV (e.g., 5-HT3 and D2), leading to the current multi-modal approach to inhibit multiple sites in this complex neural system. Despite these significant advances, there is still a lack of fundamental knowledge of the mechanisms that drive the hindbrain central pattern generator (emesis) and forebrain pathways (nausea) that produce PONV, particularly the responses to inhalational anesthesia. This gap in knowledge has limited the development of novel effective therapies of PONV. The current review presents the state of knowledge on the biological mechanisms responsible for PONV, summarizing both preclinical and clinical evidence. Finally, potential ways to advance the research of PONV and more recent developments on the study of postdischarge nausea and vomiting (PDNV) are discussed., (© 2013 Published by Elsevier B.V.)

Nausea and vomiting are biological systems for defense against food poisoning that are also provoked by numerous drugs (e.g., chemotherapy, anesthesia) and chronic diseases (e.g., cancer, diabetic gastroparesis). The sensory pathways that stimulate nausea and vomiting include vestibular, area postrema, and forebrain inputs, but gastrointestinal vagal afferent fibers arguably play the most prominent role as a first-line defense. Vagal sensory neurons detect toxins that enter the gastrointestinal lumen and transmit information to the hindbrain, leading to nausea (an unconditioned stimulus that serves to facilitate the avoidance of offending foods) and vomiting (a mechanism to clear contents from the stomach). Despite the major importance of these systems to human physiology, progress on the biological basis of nausea and vomiting has been slow - partly because laboratory rats and mice, which represent the largest thrust of preclinical biomedical research, lack a vomiting reflex (although they appear to have indices of nausea, e.g., conditioned food aversion). Several established models are a mainstay of preclinical nausea and vomiting research in academia and pharmaceutical companies, including the dog, cat, ferret, and musk shrew. An argument is made for broader testing across species since each model possesses often unique experimental advantages and sensitivity to emetic and antiemetic agents. This review focuses on the state of knowledge on the neural pathways for nausea and vomiting, behavioral indices of nausea used in preclinical models, role of vagal afferent fibers, current antiemetic and antinausea treatments, and potential future directions.

The emetic reflex occurs as a pattern of motor responses produced by a network of neurons in the hindbrain. Despite an understanding of the sequence of motor outputs that form an emetic episode (EE), the variability in the dynamics of multiple EEs across time remains a mystery. Many clinical investigations rely on once a day patient recall of total amount of vomiting, and preclinical studies frequently report only the total number of EE per unit time. The aim of the current study was to develop novel temporal measures of emetic activation in a preclinical model. Male and female musk shrews were tested with prototypical emetic stimuli: motion exposure (1 Hz), nicotine (5 mg/kg, sc), and copper sulfate (120 mg/kg, ig). New emetic measures included duration (time from first to last episode), rate, standard deviation of the inter-episode interval (SD-I), and a survival analysis of emetic latency (analyzed with Cox regression). Behavioral patterns associated with emesis were also assessed using statistical temporal pattern (T-pattern) analysis to measure nausea-like behaviors (e.g., immobility). The emetic stimuli produced different levels of total EE number, duration, rate, and SD-I. A typical antiemetic, the neurokinin 1 receptor antagonist CP-99,994, suppressed the number of EEs but was less effective for reducing the duration or prolonging the emetic latency. Overall, the current study shows the use of novel dynamic behavioral measures to more comprehensively assess emesis and the impact of therapies., (© 2013.)

The vomiting (emetic) reflex is documented in numerous mammalian species, including primates and carnivores, yet laboratory rats and mice appear to lack this response. It is unclear whether these rodents do not vomit because of anatomical constraints (e.g., a relatively long abdominal esophagus) or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver), Ctenohystrica (guinea pig, nutria), and squirrel-related (mountain beaver) species. Prototypical emetic agents, apomorphine (sc), veratrine (sc), and copper sulfate (ig), failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted). These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew). Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity-key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation (resiniferatoxin and vagal afferent stimulation) compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed.

Although partially controlled with antiemetic drugs, postoperative nausea and vomiting (PONV) continues to be a problem for many patients. Clinical research suggests that opioid analgesics and volatile anesthetics are the main triggers of PONV. The aim of this study was to develop an animal model for post-anesthesia vomiting for future studies to further determine mechanisms and preclinical drug efficacy. Ferrets (N=34) were initially used because they have served as a gold standard for emesis research. Ferrets were tested with several doses of morphine, inhaled isoflurane, and a positive control injection of cisplatin (a chemotherapy agent) to induce emesis. Musk shrews (a small animal model; N=36) were also tested for emesis with isoflurane exposure. A control injection of cisplatin produced emesis in ferrets (ip, 129.8±22.0 retches; 13.7±2.3 vomits; mean±SEM). Morphine also produced a dose-response on emesis in ferrets, with maximal responses at 0.9 mg/kg (sc, 29.6±12.6 retches; 1.8±0.9, vomits). Isoflurane exposure (2-4% for 10 min to 6h exposure) failed to induce vomiting, was not associated with an increased frequency in emesis when combined with a low dose of morphine (0.1 mg/kg, sc), and failed to produce consistent effects on food and water intake. In contrast to ferrets, musk shrews were very sensitive to isoflurane-induced emesis (0.5 to 3%, 10 min exposure; up to 11.8±2.4 emetic episodes). Overall, these results indicate that ferrets will not be useful for delineating mechanisms responsible for isoflurane-induced emesis; however, musk shrews may prove to be a model for vomiting after inhalation of volatile agents., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Until recently, sensory nerve pathways from the stomach to the brain were thought to detect distension and play little role in nutritional signaling. Newer data have challenged this view, including reports on the presence of taste receptors in the gastrointestinal lumen and the stimulation of multi-unit vagal afferent activity by glutamate infusions into the stomach. However, assessing these chemosensory effects is difficult because gastric infusions typically evoke a distension-related vagal afferent response. In the current study, we recorded gastric vagal afferent activity in the rat to investigate the possibility that umami (glutamate, 150 mM) and bitter (denatonium, 10 mM) responses could be dissociated from distension responses by adjusting the infusion rate and opening or closing the drainage port in the stomach. Slow infusions of saline (5 ml over 2 min, open port) produced no significant effects on vagal activity. Using the same infusion rate, glutamate or denatonium solutions produced little or no effects on vagal afferent activity. In an attempt to reproduce a prior report that showed distention and glutamate responses, we produced a distension response by closing the exit port. Under this condition, response to the infusion of glutamate or denatonium was similar to saline. In summary, we found little or no effect of gastric infusion of glutamate or denatonium on gastric vagal afferent activity that could be distinguished from distension responses. The current results suggest that sensitivity to umami or bitter stimuli is not a common property of gastric vagal afferent fibers., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Nausea and vomiting are common symptoms in patients with many diseases, including cancer and its treatments. Although the neurological basis of vomiting is reasonably well known, an understanding of the physiology of nausea is lacking. The primary barrier to mechanistic research on the nausea system is the lack of an animal model. Indeed investigating the effects of anti-nausea drugs in pre-clinical models is difficult because the primary readout is often emesis. It is known that animals show a behavioral profile of sickness, associated with reduced feeding and movement, and possibly these general measures are signs of nausea. Studies attempting to relate the occurrence of additional behaviors to emesis have produced mixed results. Here we applied a statistical method, temporal pattern (t-pattern) analysis, to determine patterns of behavior associated with emesis. Musk shrews were injected with the chemotherapy agent cisplatin (a gold standard in emesis research) to induce acute (<24 h) and delayed (>24 h) emesis. Emesis and other behaviors were coded and tracked from video files. T-pattern analysis revealed hundreds of non-random patterns of behavior associated with emesis, including sniffing, changes in body contraction, and locomotion. There was little evidence that locomotion was inhibited by the occurrence of emesis. Eating, drinking, and other larger body movements including rearing, grooming, and body rotation, were significantly less common in emesis-related behavioral patterns in real versus randomized data. These results lend preliminary evidence for the expression of emesis-related behavioral patterns, including reduced ingestive behavior, grooming, and exploratory behaviors. In summary, this statistical approach to behavioral analysis in a pre-clinical emesis research model could be used to assess the more global effects and limitations of drugs used to control nausea and its potential correlates, including reduced feeding and activity levels.

Vomiting is a common side effect of cancer chemotherapy and many drug treatments and diseases. In animal studies, the measurement of vomiting usually requires direct observation, which is time consuming and often lacks temporal precision. Musk shrews have been used to study the neurobiology of emesis and have a rapid emetic episode (∼1 s for a sequence of retching and expulsion). The aim of the current study was to develop a method to automatically detect and characterize emetic episodes induced by the cancer chemotherapy agent cisplatin. The body contour in each video frame was tracked and normalized to a parameterized shape basis. The tracked shape was projected to a feature space that maximized the shape variations in the consecutive frames during retching. The resulting one dimensional projection was sufficient to detect most emetic episodes in the acute (peak at 2h) and delayed (peak at 54 h) phases after cisplatin treatment. Emetic episodes were relatively invariant in the number of retches (∼6.2), duration (∼1.2s), inter-retch interval (∼198 ms), and amplitude during the 72 h after cisplatin treatment. This approach should open a new vista into emesis research to permit tracking and analysis of emesis in a small animal model and facilitate the development of new antiemetic therapies. These results also yield a better understanding of the brain's central pattern generator for emesis and indicate that the retching response in the musk shrew (at ∼5.4 Hz) is the fastest ever recorded in a free-moving animal., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Nausea and emesis are common side effects of gastrointestinal disease. Reports indicate that ghrelin and endocannabinoids, agents that stimulate appetite, also reduce emesis evoked by chemotherapy treatment, which suggests that stimulation of feeding inhibits the emetic system. In the following study we conducted a more direct test of this hypothesis by determining the impact of manipulating the motivation to eat on emesis, using food restriction and refeeding. Emesis was induced in musk shrews, a commonly used animal model for emesis research, using the cancer chemotherapy agent cisplatin (20 mg/kg ip), nicotine (2 mg/kg sc), or motion (1 Hz, horizontal, 4-cm displacement), because these treatments are known to target separate emetic pathways: gut vagal afferents, area postrema, and vestibular pathways, respectively. Twenty-four hours of food restriction was sufficient to stimulate food intake, and 1 h of refeeding filled the stomach. The results indicate that food restriction, refeeding, and gastric fill had no significant effects on the amount of emesis produced by any of the emetic treatments tested here. This suggests that, although activation of the emetic system might have prominent effects on food intake, neural controls for feeding behavior do not significantly affect the neural pathways for emesis. These results may have implications for how we treat patients who experience a constellation of side effects, including nausea and emesis, since stimulating appetite may not necessarily inhibit emetic pathways.

Anticancer agents, such as cisplatin, stimulate nausea, vomiting, and behaviors indicative of malaise. Rats and mice do not possess a vomiting response, and, therefore, in these species, the ingestion of kaolin clay (a pica response) has been used as an index of malaise. In the rat, cisplatin-induced kaolin intake is inhibited by antiemetic treatments. In addition, cisplatin activates vagal afferent fibers in the gut, and kaolin intake induced by cisplatin is largely dependent on an intact vagus. Nevertheless, little is known about the brain pathways controlling pica. We investigated the role of the lateral parabrachial nucleus (lPBN), a major visceral afferent link between the hindbrain and forebrain, in cisplatin-induced c-Fos expression and pica. Injection of cisplatin (6 mg/kg ip) produced c-Fos expression in the ventrolateral (external) lPBN, a region receiving viscerosensory input. In rats with bilateral ibotenic acid lPBN lesions, cisplatin treatment substantially increased kaolin intake compared with controls ( approximately 30 g vs. approximately 5 g, respectively, over 24 h). Food intake was reduced by cisplatin treatment and by apomorphine, an emetic agent that acts centrally. Unlike cisplatin, however, apomorphine stimulated kaolin intake to a similar degree in both the lesioned and control rats, suggesting that lPBN damage neither produces nonspecific effects nor enhances malaise in general. These data suggest that lPBN-lesioned animals not only demonstrate pica after cisplatin treatment, but, in fact, show an exaggerated response that is greatly in excess of any treatment known to produce kaolin intake in rats.

The alimentary canal includes the mouth, stomach, and intestines, and is connected to the brain by thousands of chemosensory neurons. In contrast to the understanding of the lingual taste system, there is little insight into the chemosensory function of other regions of the alimentary canal. The presence of known taste receptors in the gastrointestinal tract suggests a similarity to taste mechanisms present in the oral cavity. Afferent fibers of the vagus play a prominent role in signaling the chemical contents of the gastrointestinal tract to the hindbrain and this information can be used to elicit defensive responses, such as vomiting or nutritional responses. A host of amino acids are likely detected by vagal afferent fibers, but the initial sensory transduction of these stimuli and functional significance remains a mystery. Several problems with recording the electrophysiological signals of vagal afferents are discussed, with particular reference to sampling the afferent signals from the duodenum and liver region.

Anticancer agents such as cisplatin stimulate nausea, vomiting, and behaviors indicative of malaise. Rats and mice, and probably all rodents, do not possess a vomiting response, and their ingestion of kaolin clay (a pica response) has been used as an index of malaise. Similar to the action of cisplatin on emesis in vomiting species, in the rat cisplatin activates vagal afferent fibers, and cisplatin-induced kaolin intake is largely dependent on an intact abdominal vagus. Cisplatin also stimulates Fos expression in the rat brain in areas known to play a role in emesis in other species, but it is not known whether vagal input is required for this CNS activation. In the present study, rats were given abdominal vagotomy or sham operation to test the role of an intact vagus on cisplatin-induced Fos expression 6 h after injection with saline or cisplatin (6 mg/kg, ip). Cisplatin treatment produced Fos expression in the area postrema and multiple levels of the nucleus of the solitary tract (NTS) of sham-operated rats. Vagotomy reduced cisplatin-induced Fos expression in the caudal and middle levels of the NTS and central amygdala. Furthermore, cisplatin did not significantly alter Fos expression in the spinal cord (T8-T10) before or after vagotomy. These results suggest that a defined portion of cisplatin-induced Fos expression is dependent on vagal input, with a majority of this response determined by either direct action of cisplatin or humoral factors on the CNS.

Clay consumption can occur during illness but there has been little work to understand why. To investigate whether consuming clay confers an advantage to the sick animal, we compared the recovery from illness of adult male rats with or without access to kaolin. Illness was induced by injection of 6 mg/kg, ip, cisplatin, a toxic chemotherapy agent, and recovery was assessed by changes in daily food intake, water intake, and body weight. Relative to saline-injected controls, cisplatin-injected rats reduced food and water intake and lost weight. However, those with access to kaolin ate more food and lost less body weight than did those without access to kaolin. Thus, clay consumption appeared beneficial in that it either protected the rats from illness or enhanced recovery and might prove useful as an adjunct therapy for other animals, including humans, experiencing visceral malaise.

Cancer chemotherapy drugs, such as cisplatin, potently produce nausea and vomiting. Acute effects of these treatments are partly controlled by antiemetic drugs, but the delayed effects (>24 h), especially nausea, are more difficult to treat. It is unknown what brain pathways produce this delayed sickness. Our prior data show that brain Fos expression is increased for at least 48 h after cisplatin treatment in the rat, a nonvomiting species. Here, we extend these observations by using house musk shrews (Suncus murinus), a species with an emetic response. Compared with saline injection, cisplatin treatment (30 mg/kg ip) induced Fos expression in hindbrain areas known to play a role in the generation of emesis, the dorsal motor nucleus (DMN), the area postrema, and the nucleus of the solitary tract (NTS), for up to 48 h. Cisplatin also stimulated Fos expression in the parabrachial nucleus (PBN) of the midbrain and the central nucleus of the amygdala (CeA) for at least 48 h after treatment. When animals were pretreated with the antiemetic palonosetron, a long-term serotonin type 3 (5-HT(3)) receptor antagonist, cisplatin-induced Fos expression was significantly attenuated in the NTS, DMN, and CeA at 6 h but not at 48 h. These results indicate that cisplatin activates a neural system that includes the dorsal vagal complex and forebrain in the musk shrew, which is partially suppressed by a 5-HT(3) receptor antagonist. Our findings suggest the existence of an extensive neural system that could be targeted to reduce nausea, vomiting, and malaise in cancer patients receiving chemotherapy.

Anticancer agents, such as cisplatin, induce vomiting, nausea, and anorexia. Cisplatin primarily acts on vagal afferents to produce emesis, but little is known about how this drug generates nausea and anorexia. Electrophysiology indicates that cisplatin activates vagal afferents of the common hepatic branch (CHB). Rats lack an emetic response but do ingest kaolin clay (a pica response) when made sick by toxins, and this behavior can be inhibited by antiemetic drugs. It has been postulated that pica may serve as a proxy for emesis in the rat. The goal of this study was to assess the effect of CHB or ventral gastric (Gas) or celiac (Cel) branch vagotomies on pica and anorexia produced by cisplatin in the rat. The effects of apomorphine, a dopamine receptor agonist, which induces emesis via a central mechanism, were also assessed. Cisplatin-induced pica was suppressed by CHB vagotomy (a 61% reduction) but not by Gas and Cel vagotomy. Suppression of daily food intake and body weight following cisplatin treatment was also blunted by CHB ablation but not by Gas or Cel vagotomy. No vagotomy condition exhibited altered apomorphine-induced pica. The results indicate that the CHB, which innervates primarily the duodenum, plays an important role in cisplatin-induced malaise. These data suggest that pica has sensory pathways similar to emetic systems, since a vagotomy condition inhibited cisplatin-induced pica but had no effect on apomorphine-induced pica. This investigation contributes to the delineation of the physiology of pica and neural systems involved in malaise in the nonvomiting rat.

Nausea and vomiting are important as biological systems for drug side effects, disease co-morbidities, and defenses against food poisoning. Vomiting can serve the function of emptying a noxious chemical from the gut, and nausea appears to play a role in a conditioned response to avoid ingestion of offending substances. The sensory pathways for nausea and vomiting, such as gut and vestibular inputs, are generally defined but the problem of determining the brain's final common pathway and central pattern generator for nausea and vomiting is largely unsolved. A neurophysiological analysis of brain pathways provides an opportunity to more closely determine the neurobiology of nausea and vomiting and its prodromal signs (e.g., cold sweating, salivation).

Recent advances in the knowledge of the cellular effects of arsenic have provided insights into the molecular mechanisms of arsenic-associated carcinogenesis, immunotoxicity and cardiovascular disease. In the present experiments we tested the hypothesis that the arrival of arsenic to the gastrointestinal (GI) tract is detected by the gut-brain axis, which includes hindbrain and forebrain nuclei activated by GI stimulation. As a marker of neuronal activation we measured Fos expression using immunohistochemistry. Because Fos expression in these nuclei is closely linked to the development of conditioned flavor aversion (CFA) we also tested the effect of arsenic on CFA. Our experiments indicate that arsenic ingestion is readily detected by the brain, as shown by increased Fos expression after oral administration of arsenic. Furthermore, the vagus nerve, which supplies information from the GI tract to the brain, is not involved in this response because a complete subdiaphragmatic vagotomy did not reduce the effect of arsenic on brain Fos expression, but enhanced this response. In parallel, arsenic ingestion is associated with a robust, dose-dependent CFA, which started at doses as low as 0.1 mg/kg body weight. In summary, these data indicate that arsenic given by oral administration is detected by the brain in low concentrations, and activates specific nuclei, which might trigger behavioral responses, such as CFA.

Cancer chemotherapy drugs, such as cisplatin, are extremely potent for producing nausea and vomiting. The acute effects of these treatments are partly controlled using anti-emetic drugs, but the delayed effects (>24 h), especially nausea, are much more difficult to treat. Furthermore, cisplatin induces a long-term (up to 48 h) increase in pica in rats. Pica is manifested as an increase in consumption of kaolin (clay) and is used as a measure of visceral sickness. It is unknown what brain pathways might be responsible for this sickness associated behavior. As a first attempt to define this neural system, rats were injected (i.p.) with 3, 6, or 10 mg/kg cisplatin (doses reported to produce pica) and sacrificed at 6, 24, or 48 h to determine brain Fos expression. The primary results indicate: 1) increasing the dose of cisplatin increased the magnitude and duration of brain Fos expression, 2) most excitatory effects on hindbrain nucleus of the solitary tract (NTS) and area postrema (AP) Fos expression occurred within 24 h after cisplatin injection, 3) 6 and 10 mg/kg cisplatin treatment produced large increases in Fos expression in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST), including 48 h after injection, and 4) cisplatin treatment produced little effect on Fos expression in the paraventricular and supraoptic nuclei of the hypothalamus. These results indicate that cisplatin activates a neural system that includes the dorsal vagal complex (NTS and AP), CeA, and BNST.

A shift in motivational state often produces behavioral change, but the underlying mechanisms are poorly understood. In the marine mollusc, Aplysia californica, feeding-induced transition from a hunger to satiation state leads to a slowdown and an eventual termination of feeding. Because the multifunctional feeding network generates both ingestion and the competing response, egestion, it is possible that the transition from a hunger to a satiety state is associated with network reconfiguration that results in production of fewer ingestive and more egestive responses. Chronic electrophysiological recordings in free-feeding Aplysia showed that as the meal progressed, food elicited fewer ingestive responses and simultaneously increased the number of egestive responses. Injections of Aplysia neuropeptide Y (apNPY) reduced food intake and slowed down the rate of ingestion. apNPY was localized to buccal-ganglion afferents originating in the gut-innervating esophageal nerve (EN), a nerve involved both in satiation and in the generation of egestive programs. During EN stimulation, apNPY was released in the feeding circuit. Importantly, stimulation of the cerebral-buccal interneuron-2, a command-like interneuron that is activated by food and normally elicits ingestive responses, elicited egestive responses in the presence of apNPY. This was accompanied by increased activity of the egestion-promoting interneuron B20 and decreased activity in the ingestion-promoting interneuron B40. Thus, apNPYergic reconfiguration of the feeding central pattern generator plays a role in the gradual transition from hunger to satiety states. More generally, changes in the motivational states may involve not only simple network inhibition but may also require network reconfiguration.

Nausea and vomiting occur in a large number of disease conditions and as side effects of many drug treatments, including use of analgesics and anesthesia in surgery and chemotherapy in cancer treatment. Current anti-emetics provide relief from only some sources of vomiting, with more limited benefits for the control of nausea. Elucidation of forebrain pathways that generate nausea and brainstem circuitry controlling emesis are significant obstacles for the development of effective universal anti-nausea and anti-emetic treatments.

Nausea and vomiting are amongst the most common symptoms encountered in medicine as either symptoms of diseases or side effects of treatments. In a more biological setting they are also important components of an organism's defences against ingested toxins. Identification of treatments for nausea and vomiting and reduction of emetic liability of new therapies has largely relied on the use of animal models, and although such models have proven invaluable in identification of the anti-emetic effects of both 5-hydroxytryptamine(3) and neurokinin(1) receptor antagonists selection of appropriate models is still a matter of debate. The present paper focuses on a number of controversial issues and gaps in our knowledge in the study of the physiology of nausea and vomiting including: The choice of species for the study of emesis and the underlying behavioural (e.g. neophobia), anatomical (e.g. elongated, narrow abdominal oesophagus with reduced ability to shorten) and physiological (e.g. brainstem circuitry) mechanisms that explain the lack of a vomiting reflex in certain species (e.g. rats); The choice of response to measure (emesis[retching and vomiting], conditioned flavour avoidance or aversion, ingestion of clay[pica], plasma hormone levels[e.g. vasopressin], gastric dysrhythmias) and the relationship of these responses to those observed in humans and especially to the sensation of nausea; The stimulus coding of nausea and emesis by abdominal visceral afferents and especially the vagus-how do the afferents encode information for normal postprandial sensations, nausea and finally vomiting?; Understanding the central processing of signals for nausea and vomiting is particularly problematic in the light of observations that vomiting is more readily amenable to pharmacological treatment than is nausea, despite the assumption that nausea represents "low" intensity activation of pathways that can evoke vomiting when stimulated more intensely.

It is very difficult to study the independent contributions of the afferent and efferent pathways of the subdiaphragmatic vagus to physiology and behavior. Total subdiaphragmatic vagotomy can confound the interpretation of experimental results because it destroys both afferent and efferent vagal fibers. One approach to address this problem involves producing a total ablation of afferent (or efferent) vagal fibers while retaining half of the efferent (or afferent) vagal fibers by making a unilateral rhizotomy plus contralateral subdiaphragmatic vagotomy. However, the completeness of this afferent (or efferent) lesion is based on the assumption that there are no cross-over pathways within the thoracic cavity between the vagal trunks of the rat. To directly test for the presence of vagal cross-over pathways in the rat, we recorded the compound action potentials from the ventral and dorsal trunks of the subdiaphragmatic vagus following electrical stimulation of the left or right cervical vagi. C-fiber cross-over pathways comprised an average of 9% of the total nerve responses (range was 0 to 29%, n = 20). Direct application of the anesthetic bupivacaine to the vagus completely blocked the recorded signals. The vagal cross-over pathways were also demonstrated using capsaicin as a stimulus. These results indicate the presence of thoracic cross-over pathways between vagal trunks in the rat and demonstrate that for most animals it is not possible to produce a "complete" ablation of afferent (or efferent) components of the subdiaphragmatic vagus using unilateral rhizotomy combined with contralateral subdiaphragmatic vagotomy.

Recent work in computational neuroethology has emphasized that "the brain has a body": successful adaptive behavior is not simply commanded by the nervous system, but emerges from interactions of nervous system, body, and environment. Here we continue our study of these issues in the accessory radula closer (ARC) neuromuscular system of Aplysia. The ARC muscle participates in the animal's feeding behaviors, a set of cyclical, rhythmic behaviors driven by a central pattern generator (CPG). Patterned firing of the ARC muscle's two motor neurons, B15 and B16, releases not only ACh to elicit the muscle's contractions but also peptide neuromodulators that then shape the contractions through a complex network of actions on the muscle. These actions are dynamically complex: some are fast, but some are slow, so that they are temporally uncoupled from the motor neuron firing pattern in the current cycle. Under these circumstances, how can the nervous system, through just the narrow channel of the firing patterns of the motor neurons, control the contractions, movements, and behavior in the periphery? In two earlier papers, we developed a realistic mathematical model of the B15/B16-ARC neuromuscular system and its modulation. Here we use this model to study the functional performance of the system in a realistic behavioral task. We run the model with two kinds of inputs: a simple set of regular motor neuron firing patterns that allows us to examine the entire space of patterns, and the real firing patterns of B15 and B16 previously recorded in a 2 1/2-h-long meal of 749 cycles in an intact feeding animal. These real patterns are extremely irregular. Our main conclusions are the following. 1) The modulation in the periphery is necessary for superior functional performance. 2) The components of the modulatory network interact in nonlinear, context- and task-dependent combinations for best performance overall, although not necessarily in any particular cycle. 3) Both the fast and the slow dynamics of the modulatory state make important contributions. 4) The nervous system controls different components of the periphery to different degrees. To some extent the periphery operates semiautonomously. However, the structure of the peripheral modulatory network ensures robust performance under all circumstances, even with the irregular motor neuron firing patterns and even when the parameters of the functional task are randomly varied from cycle to cycle to simulate a variable feeding environment. In the variable environment, regular firing patterns, which are fine-tuned to one particular task, fail to provide robust performance. We propose that the CPG generates the irregular firing patterns, which nevertheless are guaranteed to give robust performance overall through the actions of the peripheral modulatory network, as part of a trial-and-error feeding strategy in a variable, uncertain environment.