The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity

1990 ◽  
Vol 68 (2) ◽  
pp. 325-345 ◽  
Author(s):  
P. L. R. Andrews ◽  
C. J. Davis ◽  
S. Bingham ◽  
H. I. M. Davidson ◽  
J. Hawthorn ◽  
...  
Keyword(s):  
Nucleus Tractus Solitarius ◽  
Area Postrema ◽  
Cytotoxic Drugs ◽  
Vagal Afferents ◽  
Laboratory Animals ◽  
Receptor Antagonists ◽  
Wide Range ◽  
Vagal Afferent ◽  
Afferent Terminals ◽  
Visceral Innervation

In recent years the role of the area postrema in the emetic reflex has been predominant and the involvement of the abdominal visceral innervation has tended to be overlooked. This paper attempts to redress the balance reflex by reviewing aspects of the existing literature and complementing this with original studies from the ferret. In view of the widespread use of the ferret in studies of emesis and particularly in the characterization of the antiemetic actions of 5-HT3 receptor antagonist, the opportunity is taken to assess the suitability of this species for studies of emesis. It is concluded that the ferret is sensitive to a wide range of emetic stimuli including intragastric irritants, opiate and dopamine receptor agonists, many cytotoxic drugs, and radiation. For several stimuli it is more sensitive than other species and for radiation on the basis of its ED100 it appears to be the most sensitive of the laboratory animals studied. Using electrical stimulation of the central end of the dorsal vagal trunk in the abdomen in conscious and anaesthetized animals, the vagal afferents were shown to be capable of eliciting emesis. Using lesioning studies an involvement of the vagus in the emetic response to a number of cytotoxic drugs (e.g., cisplatinum, cyclophosphamide, mustine) and radiation was demonstrated, although the magnitude of the effect varied with the different stimuli. An attempt is made to reconcile these observations with previous studies of area postrema ablation. The problems of interpreting the effects of nerve lesions are critically discussed in light of preliminary evidence presented here that there may be a degree of plasticity in the emetic pathway following such lesions. The range of antiemetic effects of 5-HT3 receptor antagonists is reviewed and an attempt is made to identify the site(s) at which these agents act. Results are presented that suggest a link between the vagus and 5-HT3 receptor antagonism. These studies are discussed together with others and lead us to propose that (in the ferret) 5-HT3 receptor antagonists have their main antiemetic effect by acting on vagal afferent terminals in the wall of the upper gut with an additional minor site either in the nucleus tractus solitarius or presynaptically on the vagal afferent terminals in the medulla where binding sites for 5-HT3 receptor ligands have recently been demonstrated in this species.Key words: emesis, visceral nerves, vagus nerve, ferret, plasticity, serotonin antagonists.

scholarly journals Corticosterone inhibits vagal afferent glutamate release in the nucleus of the solitary tract via retrograde endocannabinoid signaling

2020 ◽  
Vol 319 (6) ◽  
pp. C1097-C1106
Author(s):  
Forrest J. Ragozzino ◽  
Rachel A. Arnold ◽  
Cody W. Kowalski ◽  
Marina I. Savenkova ◽  
Ilia N. Karatsoreos ◽  
...  
Keyword(s):  
Brain Stem ◽  
Autonomic Function ◽  
Glutamate Release ◽  
Vagal Afferents ◽  
Solitary Tract ◽  
Excitatory Neurotransmitter ◽  
Cannabinoid Type 1 Receptor ◽  
Glutamate Signaling ◽  
Vagal Afferent ◽  
Afferent Terminals

Circulating blood glucocorticoid levels are dynamic and responsive to stimuli that impact autonomic function. In the brain stem, vagal afferent terminals release the excitatory neurotransmitter glutamate to neurons in the nucleus of the solitary tract (NTS). Vagal afferents integrate direct visceral signals and circulating hormones with ongoing NTS activity to control autonomic function and behavior. Here, we investigated the effects of corticosterone (CORT) on glutamate signaling in the NTS using patch-clamp electrophysiology on brain stem slices containing the NTS and central afferent terminals from male C57BL/6 mice. We found that CORT rapidly decreased both action potential-evoked and spontaneous glutamate signaling. The effects of CORT were phenocopied by dexamethasone and blocked by mifepristone, consistent with glucocorticoid receptor (GR)-mediated signaling. While mRNA for GR was present in both the NTS and vagal afferent neurons, selective intracellular quenching of G protein signaling in postsynaptic NTS neurons eliminated the effects of CORT. We then investigated the contribution of retrograde endocannabinoid signaling, which has been reported to transduce nongenomic GR effects. Pharmacological or genetic elimination of the cannabinoid type 1 receptor signaling blocked CORT suppression of glutamate release. Together, our results detail a mechanism, whereby the NTS integrates endocrine CORT signals with fast neurotransmission to control autonomic reflex pathways.

Peripheral oxytocin activates vagal afferent neurons to suppress feeding in normal and leptin-resistant mice: a route for ameliorating hyperphagia and obesity

2015 ◽  
Vol 308 (5) ◽  
pp. R360-R369 ◽  
Author(s):  
Yusaku Iwasaki ◽  
Yuko Maejima ◽  
Shigetomo Suyama ◽  
Masashi Yoshida ◽  
Takeshi Arai ◽  
...  
Keyword(s):  
Food Intake ◽  
Nucleus Tractus Solitarius ◽  
Body Weight Gain ◽  
Vagal Afferents ◽  
Afferent Neuron ◽  
Afferent Neurons ◽  
Vagal Afferent ◽  
Fos Expression ◽  
Novel Target ◽  
Anorexigenic Effect

Oxytocin (Oxt), a neuropeptide produced in the hypothalamus, is implicated in regulation of feeding. Recent studies have shown that peripheral administration of Oxt suppresses feeding and, when infused subchronically, ameliorates hyperphagic obesity. However, the route through which peripheral Oxt informs the brain is obscure. This study aimed to explore whether vagal afferents mediate the sensing and anorexigenic effect of peripherally injected Oxt in mice. Intraperitoneal Oxt injection suppressed food intake and increased c-Fos expression in nucleus tractus solitarius to which vagal afferents project. The Oxt-induced feeding suppression and c-Fos expression in nucleus tractus solitarius were blunted in mice whose vagal afferent nerves were blocked by subdiaphragmatic vagotomy or capsaicin treatment. Oxt induced membrane depolarization and increases in cytosolic Ca2+ concentration ([Ca2+]i) in single vagal afferent neurons. The Oxt-induced [Ca2+]i increases were markedly suppressed by Oxt receptor antagonist. These Oxt-responsive neurons also responded to cholecystokinin-8 and contained cocaine- and amphetamine-regulated transcript. In obese diabetic db/db mice, leptin failed to increase, but Oxt increased [Ca2+]i in vagal afferent neurons, and single or subchronic infusion of Oxt decreased food intake and body weight gain. These results demonstrate that peripheral Oxt injection suppresses food intake by activating vagal afferent neurons and thereby ameliorates obesity in leptin-resistant db/db mice. The peripheral Oxt-regulated vagal afferent neuron provides a novel target for treating hyperphagia and obesity.

scholarly journals Delineation of vagal emetic pathways: intragastric copper sulfate-induced emesis and viral tract tracing in musk shrews

2014 ◽  
Vol 306 (5) ◽  
pp. R341-R351 ◽  
Author(s):  
Charles C. Horn ◽  
Kelly Meyers ◽  
Audrey Lim ◽  
Matthew Dye ◽  
Diana Pak ◽  
...  
Keyword(s):  
Copper Sulfate ◽  
Area Postrema ◽  
Food Poisoning ◽  
Small Animal ◽  
Brain Regions ◽  
Afferent Input ◽  
Vagal Afferents ◽  
Anterograde Transport ◽  
Neural Tracing ◽  
Vagal Afferent

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.

NMDA channels control meal size via central vagal afferent terminals

2005 ◽  
Vol 289 (5) ◽  
pp. R1504-R1511 ◽  
Author(s):  
B. R. Gillespie ◽  
G. A. Burns ◽  
R. C. Ritter
Keyword(s):  
Food Intake ◽  
Ion Channel ◽  
Nmda Receptors ◽  
Higher Order ◽  
Meal Size ◽  
Vagal Afferents ◽  
Sucrose Intake ◽  
Mk 801 ◽  
Vagal Afferent ◽  
Afferent Terminals

The N-methyl-d-aspartate (NMDA) ion channel blocker MK-801 administered systemically or as a nanoliter injection into the nucleus of the solitary tract (NTS), increases meal size. Furthermore, we have observed that ablation of the NTS abolishes increased meal size following systemic injection of dizocilpine (MK-801) and that MK-801-induced increases in intake are attenuated in rats pretreated with capsaicin to destroy small, unmyelinated, primary afferent neurons. These findings led us to hypothesize that NMDA receptors on central vagal afferent terminals or on higher-order NTS neurons innervated by these vagal afferents might mediate increased food intake. To evaluate this hypothesis, we examined 15% sucrose intake after 50-nl MK-801 injections ipsilateral or contralateral to unilateral nodose ganglion removal (ganglionectomy). On the side contralateral to ganglionectomy, vagal afferent terminals would be intact and functional, whereas ipsilateral to ganglionectomy vagal afferent terminals would be absent. Three additional control preparations also were included: 1) sham ganglionectomy and 2) subnodose vagotomy either contralateral or ipsilateral to NTS cannula placement. We found that rats with subnodose vagotomies increased their sucrose intake after injections of MK-801 compared with saline, regardless of whether injections were made contralateral (12.6 ± 0.2 vs. 9.6 ± 0.3 ml) or ipsilateral (14.2 ± 0.6 vs. 9.7 ± 0.4 ml) to vagotomy. Rats with NTS cannula placements contralateral to nodose ganglionectomy also increased their intake after MK-801 (12.2 ± 0.9 and 9.2 ± 1.1 ml for MK-801 and saline, respectively). However, rats with placements ipsilateral to ganglionectomy did not respond to MK-801 (8.0 ± 0.5 ml) compared with saline (8.3 ± 0.4 ml). We conclude that central vagal afferent terminals are necessary for increased food intake in response to NMDA ion channel blockade. The function of central vagal afferent processes or the activity of higher-order NTS neurons driven by vagal afferents may be modulated by NMDA receptors to control meal size.

scholarly journals Neurons in the Nucleus Tractus Solitarius are Selective to the Orientation of Gastric Electrical Stimulation

2021 ◽  
Author(s):  
Jiayue Cao ◽  
Xiaokai Wang ◽  
Terry L Powley ◽  
Zhongming Liu
Keyword(s):  
Smooth Muscle ◽  
Electrical Stimulation ◽  
Nucleus Tractus Solitarius ◽  
Functional Gastrointestinal Disorders ◽  
Smooth Muscles ◽  
Gastric Electrical Stimulation ◽  
Vagal Afferents ◽  
Stimulus Orientation ◽  
Afferent Neurons ◽  
Vagal Afferent

Gastric electrical stimulation (GES) is a bioelectric intervention for gastroparesis, obesity, and other functional gastrointestinal disorders. In a potential mechanism of action, GES activates the nerve endings of vagal afferent neurons and induces the vago-vagal reflex through the nucleus tractus solitarius (NTS) in the brainstem. However, it is unclear where and how to stimulate in order to optimize the vagal afferent responses. To address this question with electrophysiology in rats, we applied mild electrical currents to two serosal targets on the distal forestomach with dense distributions of vagal intramuscular arrays that innervated the circular and longitudinal smooth muscle layers. During stimulation, we recorded single and multi-unit responses in NTS and evaluated how the recorded responses depended on the stimulus orientation and amplitude. We found that NTS responses were highly selective to the stimulus orientation for a range of stimulus amplitudes. The strongest responses were observed when the applied current flowed in the same direction as the intramuscular arrays in parallel with the underlying smooth muscle fibers. Our results suggest that gastric neurons in NTS may encode the orientation-specific activity of gastric smooth muscles relayed by vagal afferent neurons. This finding suggests that the orientation of GES is critical to effective engagement of vagal afferents and should be considered in light of the structural phenotypes of vagal terminals in the stomach.

scholarly journals Loss of neurotrophin-3 from smooth muscle disrupts vagal gastrointestinal afferent signaling and satiation

2013 ◽  
Vol 305 (11) ◽  
pp. R1307-R1322 ◽  
Author(s):  
Edward A. Fox ◽  
Jessica E. Biddinger ◽  
Zachary C. Baquet ◽  
Kevin R. Jones ◽  
Jennifer McAdams
Keyword(s):  
Smooth Muscle ◽  
Area Postrema ◽  
Microstructural Analysis ◽  
Meal Size ◽  
Vagal Afferents ◽  
Eating Rate ◽  
Daily Food ◽  
Neurotrophin 3 ◽  
Vagal Afferent ◽  
Afferent Signaling

A large proportion of vagal afferents are dependent on neurotrophin-3 (NT-3) for survival. NT-3 is expressed in developing gastrointestinal (GI) smooth muscle, a tissue densely innervated by vagal mechanoreceptors, and thus could regulate their survival. We genetically ablated NT-3 from developing GI smooth muscle and examined the pattern of loss of NT-3 expression in the GI tract and whether this loss altered vagal afferent signaling or feeding behavior. Meal-induced c-Fos activation was reduced in the solitary tract nucleus and area postrema in mice with a smooth muscle-specific NT-3 knockout ( SM-NT-3 KO) compared with controls, suggesting a decrease in vagal afferent signaling. Daily food intake and body weight of SM-NT-3 KO mice and controls were similar. Meal pattern analysis revealed that mutants, however, had increases in average and total daily meal duration compared with controls. Mutants maintained normal meal size by decreasing eating rate compared with controls. Although microstructural analysis did not reveal a decrease in the rate of decay of eating in SM-NT-3 KO mice, they ate continuously during the 30-min meal, whereas controls terminated feeding after 22 min. This led to a 74% increase in first daily meal size of SM-NT-3 KO mice compared with controls. The increases in meal duration and first meal size of SM-NT-3 KO mice are consistent with reduced satiation signaling by vagal afferents. This is the first demonstration of a role for GI NT-3 in short-term controls of feeding, most likely involving effects on development of vagal GI afferents that regulate satiation.

Peripheral versus central modulation of gastric vagal pathways by metabotropic glutamate receptor 5

2007 ◽  
Vol 292 (2) ◽  
pp. G501-G511 ◽  
Author(s):  
Richard L. Young ◽  
Amanda J. Page ◽  
Tracey A. O'Donnell ◽  
Nicole J. Cooper ◽  
L. Ashley Blackshaw
Keyword(s):  
Lower Esophageal Sphincter ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Nucleus Tractus Solitarius ◽  
Vagal Afferents ◽  
Proximal Stomach ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Vagal Afferent ◽  
Esophageal Sphincter

Metabotropic glutamate receptors (mGluR) are classified into group I, II, and III mGluR. Group I (mGluR1, mGluR5) are excitatory, whereas group II and III are inhibitory. mGluR5 antagonism potently reduces triggering of transient lower esophageal sphincter relaxations and gastroesophageal reflux. Transient lower esophageal sphincter relaxations are mediated via a vagal pathway and initiated by distension of the proximal stomach. Here, we determined the site of action of mGluR5 in gastric vagal pathways by investigating peripheral responses of ferret gastroesophageal vagal afferents to graded mechanical stimuli in vitro and central responses of nucleus tractus solitarius (NTS) neurons with gastric input in vivo in the presence or absence of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). mGluR5 were also identified immunohistochemically in the nodose ganglia and NTS after extrinsic vagal inputs had been traced from the proximal stomach. Gastroesophageal vagal afferents were classified as mucosal, tension, or tension-mucosal (TM) receptors. MPEP (1–10 μM) inhibited responses to circumferential tension of tension and TM receptors. Responses to mucosal stroking of mucosal and TM receptors were unaffected. MPEP (0.001–10 nmol icv) had no major effect on the majority of NTS neurons excited by gastric distension or on NTS neurons inhibited by distension. mGluR5 labeling was abundant in gastric vagal afferent neurons and sparse in fibers within NTS vagal subnuclei. We conclude that mGluR5 play a prominent role at gastroesophageal vagal afferent endings but a minor role in central gastric vagal pathways. Peripheral mGluR5 may prove a suitable target for reducing mechanosensory input from the periphery, for therapeutic benefit.

Area postrema and aortic or vagal afferents converge to excite cells in nucleus tractus solitarius

1993 ◽  
Vol 264 (5) ◽  
pp. H1674-H1685 ◽  
Author(s):  
A. C. Bonham ◽  
E. M. Hasser
Keyword(s):  
Response Rate ◽  
Nucleus Tractus Solitarius ◽  
Area Postrema ◽  
Unit Response ◽  
Vagal Afferents ◽  
Afferent Pathways ◽  
Simple Addition ◽  
Aortic Depressor Nerve ◽  
Alpha Chloralose ◽  
Extracellular Activity

Area postrema neurons enhance baroreflex function, perhaps by augmenting baroreceptor afferent processing in the nucleus tractus solitarius (NTS). If so, NTS neurons should receive convergent excitatory inputs from area postrema neurons and baroreceptors. The aims of this study were to record extracellular activity of NTS neurons to determine whether 1) area postrema and aortic baroreceptor afferents converged in NTS, 2) area postrema and vagal afferents converged in NTS, and 3) the convergent inputs were facilitative. Studies were performed in pentobarbital sodium- or alpha-chloralose-anesthetized rabbits. Forty-six of 194 NTS neurons received inputs from the area postrema and aortic depressor nerve. Twelve of the 23 inputs showed facilitative summation; unit response rate evoked by paired inputs (79%) doubled the predicted (calculated) response rate for simple addition (37%). Fifty-eight of 114 NTS neurons received excitatory inputs from the area postrema and vagus. Eleven of the 13 inputs showed facilitative summation; unit response to paired inputs (87%) doubled the predicted response (44%). Area postrema neurons may augment the processing of aortic and vagal inputs by NTS neurons and, hence, enhance the reflex output of these afferent pathways.

Electrophysiological evidence that systemic angiotensin influences rat area postrema neurons

1990 ◽  
Vol 258 (1) ◽  
pp. R70-R76 ◽  
Author(s):  
S. Papas ◽  
P. Smith ◽  
A. V. Ferguson
Keyword(s):  
Nucleus Tractus Solitarius ◽  
Area Postrema ◽  
Cell Types ◽  
Male Rats ◽  
Ang Ii ◽  
Adrenergic Agonist ◽  
Arterial Blood ◽  
Spontaneous Activities ◽  
Single Unit Recordings ◽  
Body Fluid Balance

Extracellular single-unit recordings from neurons in the area postrema (AP) and the nucleus tractus solitarius (NTS) in anesthetized male rats demonstrated that most cells in these regions have spontaneous activities of 5 Hz or less. Systemic angiotensin (ANG II) (50-500 ng) enhanced the activity of 55% of AP cells tested (n = 76), whereas 53% of tested NTS neurons (n = 62) were inhibited by ANG II. To determine whether these neurons were influenced specifically by circulating ANG II or by the accompanying increase in mean arterial blood pressure (BP), the effects of adrenergic agonists given intravenously on ANG II influenced neurons were also examined. Subsequently two cell types were characterized: cells responding to iv ANG II but not to the adrenergic agonist ("ANG II sensitive") and cells responding in a similar way to both agents ("BP sensitive"). Most ANG II-responsive neurons in the AP (53.5%) and the NTS (65%) were determined to be BP sensitive. These data demonstrate that ANG II influences the activity of AP neurons. In addition, there exists a second population of AP neurons apparently responsive to perturbations of the cardiovascular system. These studies further emphasize the potential roles of the AP in the regulation of body fluid balance.

scholarly journals Evidence of activation of vagal afferents by non-invasive vagus nerve stimulation: An electrophysiological study in healthy volunteers

Cephalalgia ◽  
2017 ◽  
Vol 37 (13) ◽  
pp. 1285-1293 ◽  
Author(s):  
Romain Nonis ◽  
Kevin D’Ostilio ◽  
Jean Schoenen ◽  
Delphine Magis
Keyword(s):  
Vagus Nerve ◽  
Healthy Volunteers ◽  
Nerve Stimulation ◽  
Vagus Nerve Stimulation ◽  
Electrophysiological Study ◽  
Vagal Afferents ◽  
Response Analysis ◽  
Bipolar Electrode ◽  
Non Invasive ◽  
Vagal Afferent

Background Benefits of cervical non-invasive vagus nerve stimulation (nVNS) devices have been shown in episodic cluster headache and preliminarily suggested in migraine, but direct evidence of vagus nerve activation using such devices is lacking. Vagal somatosensory evoked potentials (vSEPs) associated with vagal afferent activation have been reported for invasive vagus nerve stimulation (iVNS) and non-invasive auricular vagal stimulation. Here, we aimed to show and characterise vSEPs for cervical nVNS. Methods vSEPs were recorded for 12 healthy volunteers who received nVNS over the cervical vagus nerve, bipolar electrode/DS7A stimulation over the inner tragus, and nVNS over the sternocleidomastoid (SCM) muscle. We measured peak-to-peak amplitudes (P1-N1), wave latencies, and N1 area under the curve. Results P1-N1 vSEPs were observed for cervical nVNS (11/12) and auricular stimulation (9/12), with latencies similar to those described previously, whereas SCM stimulation revealed only a muscle artefact with a much longer latency. A dose-response analysis showed that cervical nVNS elicited a clear vSEP response in more than 80% of the participants using an intensity of 15 V. Conclusion Cervical nVNS can activate vagal afferent fibres, as evidenced by the recording of far-field vSEPs similar to those seen with iVNS and non-invasive auricular stimulation.

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