CCK enhances response to gastric distension by acting on capsaicin-insensitive vagal afferents

2005 ◽  
Vol 289 (3) ◽  
pp. R695-R703 ◽  
Author(s):  
E. H. E. M. van de Wall ◽  
P. Duffy ◽  
R. C. Ritter
Keyword(s):  
Vagal Afferents ◽  
Gastric Distension ◽  
Solitary Tract ◽  
C Fibers ◽  
Balloon Distension ◽  
Electrophysiological Responses ◽  
Vagal Afferent ◽  
Fos Expression ◽  
Afferent Response ◽  
And Control

Capsaicin treatment destroys vagal afferent C fibers and markedly attenuates reduction of food intake and induction of hindbrain Fos expression by CCK. However, both anatomical and electrophysiological data indicate that some gastric vagal afferents are not destroyed by capsaicin. Because CCK enhances behavioral and electrophysiological responses to gastric distension in rats and people, we hypothesized that CCK might enhance the vagal afferent response to gastric distension via an action on capsaicin-insensitive vagal afferents. To test this hypothesis, we quantified expression of Fos-like immunoreactivity (Fos) in the dorsal vagal complex (DVC) of capsaicin-treated (Cap) and control rats (Veh), following gastric balloon distension alone and in combination with CCK injection. In Veh rats, intraperitoneal CCK significantly increased DVC Fos, especially in nucleus of the solitary tract (NTS), whereas in Cap rats, CCK did not significantly increase DVC Fos. In contrast to CCK, gastric distension did significantly increase Fos expression in the NTS of both Veh and Cap rats, although distension-induced Fos was attenuated in Cap rats. When CCK was administered during gastric distension, it significantly enhanced NTS Fos expression in response to distension in Cap rats. Furthermore, CCK's enhancement of distension-induced Fos in Cap rats was reversed by the selective CCK-A receptor antagonist lorglumide. We conclude that CCK directly activates capsaicin-sensitive C-type vagal afferents. However, in capsaicin-resistant A-type afferents, CCK's principal action may be facilitation of responses to gastric distension.

scholarly journals The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1

2011 ◽  
Vol 301 (5) ◽  
pp. R1479-R1485 ◽  
Author(s):  
Matthew R. Hayes ◽  
Scott E. Kanoski ◽  
Bart C. De Jonghe ◽  
Theresa M. Leichner ◽  
Amber L. Alhadeff ◽  
...  
Keyword(s):  
Food Intake ◽  
Vagal Afferents ◽  
Oral Glucose ◽  
Afferent Fibers ◽  
The Common ◽  
Vagal Afferent ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
And Control ◽  
Hepatic Branch

The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. Central nervous system processing of GLP-1R-driven vagal afferents results in satiation signaling and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal l-cells following ingestion, it stands to reason that paracrine GLP-1 signaling, activating adjacent GLP-1R expressed on vagal afferent fibers of gastrointestinal origin, contributes to glycemic and food intake control. However, systemic GLP-1R-mediated control of glycemia is currently attributed to endocrine action involving GLP-1R expressed in the hepatoportal bed on terminals of the common hepatic branch of the vagus (CHB). Here, we examine the hypothesis that activation of GLP-1R expressed on the CHB is not required for GLP-1's glycemic and intake suppressive effects, but rather paracrine signaling on non-CHB vagal afferents is required to mediate GLP-1's effects. Selective CHB ablation (CHBX), complete subdiaphragmatic vagal deafferentation (SDA), and surgical control rats received an oral glucose tolerance test (2.0 g glucose/kg) 10 min after an intraperitoneal injection of the GLP-1R antagonist, exendin-(9–39) (Ex-9; 0.5 mg/kg) or vehicle. CHBX and control rats showed comparable increases in blood glucose following blockade of GLP-1R by Ex-9, whereas SDA rats failed to show a GLP-1R-mediated incretin response. Furthermore, GLP-1(7–36) (0.5 mg/kg ip) produced a comparable suppression of 1-h 25% glucose intake in both CHBX and control rats, whereas intake suppression in SDA rats was blunted. These findings support the hypothesis that systemic GLP-1R mediation of glycemic control and food intake suppression involves paracrine-like signaling on GLP-1R expressed on vagal afferent fibers of gastrointestinal origin but does not require the CHB.

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.

GABAB receptors on vagal afferent pathways: peripheral and central inhibition

2001 ◽  
Vol 280 (4) ◽  
pp. G658-G668 ◽  
Author(s):  
Elita R. Partosoedarso ◽  
Richard L. Young ◽  
L. Ashley Blackshaw
Keyword(s):  
Brain Stem ◽  
Gabab Receptors ◽  
Vagal Afferents ◽  
Gastric Distension ◽  
Neuronal Responses ◽  
Afferent Pathways ◽  
Central Inhibition ◽  
Vagal Afferent ◽  
Vagal Efferents ◽  
Cgp 35348

To investigate GABAB receptors along vagal afferent pathways, we recorded from vagal afferents, medullary neurons, and vagal efferents in ferrets. Baclofen (7–14 μmol/kg iv) reduced gastric tension receptor and nucleus tractus solitarii neuronal responses to gastric distension but not gastroduodenal mucosal receptor responses to cholecystokinin (CCK). GABAB antagonists CGP-35348 or CGP-62349 reversed effects of baclofen. Vagal efferents showed excitatory and inhibitory responses to distension and CCK. Baclofen (3 nmol icv or 7–14 μmol/kg iv) reduced both distension response types but reduced only inhibitory responses to CCK. CGP-35348 (100 nmol icv or 100 μmol/kg iv) reversed baclofen's effect on distension responses, but inhibitory responses to CCK remained attenuated. They were, however, reversed by CGP-62349 (0.4 nmol icv). In conclusion, GABAB receptors inhibit mechanosensitivity, not chemosensitivity, of vagal afferents peripherally. Mechanosensory input to brain stem neurons is also reduced centrally by GABAB receptors, but excitatory chemosensory input is unaffected. Inhibitory mechano- and chemosensory inputs to brain stem neurons (via inhibitory interneurons) are both reduced, but the pathway taken by chemosensory input involves GABAB receptors that are insensitive to CGP-35348.

scholarly journals Subdiaphragmatic vagal afferent nerves modulate visceral pain

2008 ◽  
Vol 294 (6) ◽  
pp. G1441-G1449 ◽  
Author(s):  
S. L. Chen ◽  
X. Y. Wu ◽  
Z. J. Cao ◽  
J. Fan ◽  
M. Wang ◽  
...  
Keyword(s):  
Vagus Nerve ◽  
High Intensity ◽  
Visceral Pain ◽  
Light Level ◽  
Vagal Afferents ◽  
Abdominal Muscles ◽  
Low Intensity ◽  
C Fibers ◽  
Afferent Nerves ◽  
Vagal Afferent

Activation of the vagal afferents by noxious gastrointestinal stimuli suggests that vagal afferents may play a complex role in visceral pain processes. The contribution of the vagus nerve to visceral pain remains unresolved. Previous studies reported that patients following chronic vagotomy have lower pain thresholds. The patient with irritable bowel syndrome has been shown alteration of vagal function. We hypothesize that vagal afferent nerves modulate visceral pain. Visceromotor responses (VMR) to graded colorectal distension (CRD) were recorded from the abdominal muscles in conscious rats. Chronic subdiaphragmatic vagus nerve sections induced 470, 106, 51, and 54% increases in VMR to CRD at 20, 40, 60 and 80 mmHg, respectively. Similarly, at light level of anesthesia, topical application of lidocaine to the subdiaphragmatic vagus nerve in rats increased VMR to CRD. Vagal afferent neuronal responses to low or high-intensity electrical vagal stimulation (EVS) of vagal afferent Aδ or C fibers were distinguished by calculating their conduction velocity. Low-intensity EVS of Aδ fibers (40 μA, 20 Hz, 0.5 ms for 30 s) reduced VMR to CRD at 40, 60, and 80 mmHg by 41, 52, and 58%, respectively. In contrast, high-intensity EVS of C fibers (400 μA, 1 Hz, 0.5 ms for 30 s) had no effect on VMR to CRD. In conclusion, we demonstrated that vagal afferent nerves modulate visceral pain. Low-intensity EVS that activates vagal afferent Aδ fibers reduced visceral pain. Thus EVS may potentially have a role in the treatment of chronic visceral pain.

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.

Effect of vagal and splanchnic nerve section on Fos expression in ferret brain stem after emetic stimuli

1996 ◽  
Vol 271 (1) ◽  
pp. R228-R236 ◽  
Author(s):  
F. M. Boissonade ◽  
J. S. Davison
Keyword(s):  
Vagus Nerve ◽  
Brain Stem ◽  
Area Postrema ◽  
Splanchnic Nerve ◽  
Vagal Afferents ◽  
Sham Operation ◽  
Relative Importance ◽  
Solitary Tract ◽  
Nerve Section ◽  
Fos Expression

Previous studies have demonstrated that intraduodenal hypertonic saline (IHS) induces dense Fos expression within two regions of the ferret dorsal vagal complex (DVC): the area postrema (AP) and the medial subnucleus of the nucleus of the solitary tract (mn). The aims of the present experiments were to determine the peripheral pathways involved in excitation of DVC neurons after IHS and the relative importance of mn and AP excitation in the emetic response to this stimulus. The emetic response and the distribution of Fos were examined after IHS in animals that had received either vagotomy alone, vagotomy and splanchnic nerve section, or sham operation. The emetic response was studied in both awake and anesthetized animals, and Fos induction was studied in anesthetized animals. Vagotomy alone or combined with splanchnic nerve section abolished the emetic response and the area of dense labeling within the mn and reduced but did not abolish the labeling in the AP. It was concluded that both the emetic reflex and the dense expression of Fos within the mn after IHS are dependent on an intact vagus nerve. The excitation of neurons in the AP after IHS is partially dependent on vagal afferents, and the residual labeling that is present in the AP of neurectomized animals may be mediated via a blood-borne route.

Duodenal nutrient infusions differentially affect sham feeding and Fos expression in rat brain stem

1998 ◽  
Vol 274 (6) ◽  
pp. R1725-R1733 ◽  
Author(s):  
Curtis B. Phifer ◽  
Hans-Rudolf Berthoud
Keyword(s):  
Amino Acids ◽  
Linoleic Acid ◽  
Area Postrema ◽  
Gastric Distension ◽  
Acid Mixture ◽  
Neural Pathways ◽  
Solitary Tract ◽  
Sham Feeding ◽  
Caloric Value ◽  
Fos Expression

Duodenal infusions of macronutrients inhibit sham and normal feeding. Neural substrates of this response were studied by infusing glucose, linoleic acid, an amino acid mixture, saline, or water into the duodenum of unanesthetized rats and then measuring sham feeding of 30% sucrose or Fos expression in the dorsal vagal complex. Linoleic acid and amino acids (both 1.5 kcal) and glucose (4.5 kcal) suppressed sham feeding relative to control infusions, and all three macronutrients triggered Fos expression in the nucleus of the solitary tract and area postrema. Although there were significant quantitative differences, the subnuclear distribution pattern of Fos-expressing neurons was not different for the three macronutrients and was largely localized to the medial, dorsomedial, and commissural subnuclei of the nucleus of the solitary tract and the area postrema. Linoleic acid suppressed intake and stimulated Fos expression similarly to glucose infusions of three times the caloric value. Amino acids strongly suppressed sham feeding but triggered relatively little Fos expression. These results indicate that the intake-suppressing potency of duodenal macronutrients is dependent on nutrient type, rather than simply caloric value, and that amino acids, although potent inducers of satiety, affect ingestion by processes different from those subserving lipids and carbohydrates. Furthermore, the similar patterns of neuronal activation after different duodenal infusions may indicate a large degree of convergence at the level of primary and second-order sensory neurons, whereas the distinctly different pattern obtained earlier with gastric distension indicates partially separate neural pathways for satiety signals generated by duodenal nutrients and gastric mechanoreceptors.

Gastric loads and cholecystokinin synergistically stimulate rat gastric vagal afferents

1993 ◽  
Vol 265 (4) ◽  
pp. R872-R876 ◽  
Author(s):  
G. J. Schwartz ◽  
P. R. McHugh ◽  
T. H. Moran
Keyword(s):  
Food Intake ◽  
Vagal Afferents ◽  
Sufficient Information ◽  
Afferent Activity ◽  
Combined Load ◽  
Synergistic Inhibition ◽  
Afferent Fibers ◽  
Inhibit Food Intake ◽  
Vagal Afferent ◽  
Afferent Response

Both gastric preloads and exogenous cholecystokinin (CCK) administration inhibit food intake, and combinations of preloads and CCK suppress feeding to a greater degree than either stimulus delivered alone. A role for the vagus nerve in mediating CCK's inhibition of food intake has been proposed, and gastric vagal afferent fibers respond to both gastric loads and local CCK infusions. To examine whether combined load and CCK stimuli may synergistically augment gastric neural afferent activity at the level of the peripheral vagus, we have examined the gastric vagal afferent responses (n = 8) to a range of gastric saline loads (1, 2, and 3 ml) and exogenous close celiac arterial CCK (10 and 100 pmol) when administered alone or in combination. Gastric loads ineffective in eliciting a significant increase in vagal afferent activity when administered alone became effective when combined with doses of CCK that were subthreshold for the production of a vagal afferent response. Gastric loads that alone were effective in producing a significant vagal afferent response yielded an even greater response when administered in combination with both subthreshold and suprathreshold doses of CCK. These data demonstrate that, in rats, signals produced by combined gastric load and exogenous CCK administration are integrated peripherally and interact synergistically. These results suggest that signals arising from the vagus may provide sufficient information for the synergistic inhibition of food intake produced by combinations of gastric loads and exogenous CCK.

scholarly journals Cooperative Activation of Cultured Vagal Afferent Neurons by Leptin and Cholecystokinin

Endocrinology ◽  
2004 ◽  
Vol 145 (8) ◽  
pp. 3652-3657 ◽  
Author(s):  
J. H. Peters ◽  
A. B. Karpiel ◽  
R. C. Ritter ◽  
S. M. Simasko
Keyword(s):  
Primary Cultures ◽  
Cytosolic Calcium ◽  
Extracellular Calcium ◽  
Vagal Afferents ◽  
Afferent Neurons ◽  
Adult Rat ◽  
Nodose Ganglia ◽  
Vagal Afferent ◽  
Acute Changes ◽  
And Control

Abstract To test the hypothesis that leptin can directly activate vagal afferent neurons, we used fluorescence imaging to detect acute changes in cytosolic calcium after leptin application to primary cultures of vagal afferent neurons dissociated from adult rat nodose ganglia. We found that approximately 40% of vagal afferent neurons exposed to leptin (40 ng/ml) responded with rapid and reversible increases in cytosolic calcium. These responses were dependent upon extracellular calcium. As previously reported, about 35% of vagal afferents increase cytosolic calcium in response to the gut-peptide cholecystokinin (CCK). A majority (74%) of neurons that responded to CCK also exhibited increases in cytosolic calcium in response to leptin. In addition, synergistic increases in cytosolic calcium were observed when leptin and CCK were applied in combination. These results demonstrate that leptin acts directly on vagal afferent neurons to trigger acute influxes of extracellular calcium. Our results also suggest cooperation between leptin and CCK in the activation of some vagal afferent neurons. Acute activation of vagal afferents by leptin alone and in combination with CCK may contribute to modulation of visceral reflexes and control of food intake.

Targeted disruption of the murine CCK1 receptor gene reduces intestinal lipid-induced feedback inhibition of gastric function

2006 ◽  
Vol 291 (1) ◽  
pp. G156-G162 ◽  
Author(s):  
K. L. Whited ◽  
D. Thao ◽  
K. C. Kent Lloyd ◽  
A. S. Kopin ◽  
H. E. Raybould
Keyword(s):  
Gastric Emptying ◽  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Feedback Inhibition ◽  
Vagal Afferents ◽  
Afferent Pathway ◽  
Gastric Function ◽  
Vagal Afferent ◽  
Fos Expression

Cholecystokinin (CCK), acting at CCK1 receptors (CCK1Rs) on intestinal vagal afferent terminals, has been implicated in the control of gastrointestinal function and food intake. Using CCK1R−/− mice, we tested the hypothesis that lipid-induced activation of the vagal afferent pathway and intestinal feedback of gastric function is CCK1R dependent. In anesthetized CCK1R+/+ (“wild type”) mice, meal-stimulated gastric acid secretion was inhibited by intestinal lipid infusion; this was abolished in CCK1R−/− mice. Gastric emptying of whole egg, measured by nuclear scintigraphy in awake mice, was significantly faster in CCK1R−/− than CCK1R+/+ mice. Gastric emptying of chow was significantly slowed in response to administration of CCK-8 (22 pmol) in CCK1R+/+ but not CCK1R−/− mice. Activation of the vagal afferent pathway was measured by immunohistochemical localization of Fos protein in the nucleus of the solitary tract (NTS; a region where vagal afferents terminate). CCK-8 (22 pmol ip) increased neuronal Fos expression in the NTS of fasted CCK1R+/+ mice; CCK-induced Fos expression was reduced by 97% in CCK1R−/− compared with CCK1R+/+ mice. Intralipid (0.2 ml of 20% Intralipid and 0.04 g lipid), but not saline, gavage increased Fos expression in the NTS of fasted CCK1R+/+ mice; lipid-induced Fos expression was decreased by 47% in CCK1R−/− compared with CCK1R+/+mice. We conclude that intestinal lipid activates the vagal afferent pathway, decreases gastric acid secretion, and delays gastric emptying via a CCK1R-dependent mechanism. Thus, despite a relatively normal phenotype, intestinal feedback in response to lipid is severely impaired in these mice.

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