Inhibition of gastric motility by application of nicotine into the dorsal motor nucleus of vagus in rats

Previous studies have demonstrated the efficacy of electroacupuncture at ST36 for patients with gastrointestinal motility disorders. While several lines of evidence suggest that the effect may involve vagal reflex, the precise molecular mechanism underlying this process still remains unclear. Here we report that the intragastric pressure increase induced by low frequency electric stimulation at ST36 was blocked by AP-5, an antagonist of N-methyl-D-aspartate receptors (NMDARs). Indeed, stimulating ST36 enhanced NMDAR-mediated, but not 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic-acid-(AMPA-) receptor-(AMPAR-) mediated synaptic transmission in gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV). We also identified that suppression of presynapticμ-opioid receptors may contribute to upregulation of NMDAR-mediated synaptic transmission induced by electroacupuncture at ST36. Furthermore, we determined that the glutamate-receptor-2a-(NR2A-) containing NMDARs are essential for NMDAR-mediated enhancement of gastric motility caused by stimulating ST36. Taken together, our results reveal an important role of NMDA receptors in mediating enhancement of gastric motility induced by stimulating ST36.

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A reevaluation of the effects of stimulation of the dorsal motor nucleus of the vagus on gastric motility in the rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00863.2005 ◽

2007 ◽

Vol 292 (1) ◽

pp. R291-R307 ◽

Cited By ~ 34

Author(s):

Maureen T. Cruz ◽

Erin C. Murphy ◽

Niaz Sahibzada ◽

Joseph G. Verbalis ◽

Richard A. Gillis

Keyword(s):

Gastric Motility ◽

Intragastric Balloon ◽

Motor Nucleus ◽

Inhibitory Effects ◽

Inhibitory Pathways ◽

Dorsal Motor Nucleus ◽

Bilateral Vagotomy ◽

Oxide Synthase ◽

Intravenous Atropine ◽

Stimulation Of

Our primary purpose was to characterize vagal pathways controlling gastric motility by microinjecting l-glutamate into the dorsal motor nucleus of the vagus (DMV) in the rat. An intragastric balloon was used to monitor motility. In 39 out of 43 experiments, microinjection of l-glutamate into different areas of the DMV rostral to calamus scriptorius (CS) resulted in vagally mediated excitatory effects on motility. We observed little evidence for inhibitory effects, even with intravenous atropine or with activation of gastric muscle muscarinic receptors by intravenous bethanechol. Inhibition of nitric oxide synthase with Nω-nitro-l-arginine methyl ester (l-NAME) HCl did not augment DMV-evoked excitatory effects on gastric motility. Microinjection of l-glutamate into the DMV caudal to CS produced vagally mediated gastric inhibition that was resistant to l-NAME. l-Glutamate microinjected into the medial subnucleus of the tractus solitarius (mNTS) also produced vagally mediated inhibition of gastric motility. Motility responses evoked from the DMV were always blocked by ipsilateral vagotomy, while responses evoked from the mNTS required bilateral vagotomy to be blocked. Microinjection of oxytocin into the DMV inhibited gastric motility, but the effect was never blocked by ipsilateral vagotomy, suggesting that the effect may have been due to diffusion of oxytocin to the mNTS. Microinjection of substance P and N-methyl-d-aspartate into the DMV also produced inhibitory effects attributable to excitation of nearby mNTS neurons. Our results do not support previous studies indicating parallel vagal excitatory and inhibitory pathways originating in the DMV rostral to CS. Our results do support previous findings of vagal inhibitory pathways originating in the DMV caudal to CS.

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Neurons in the vagal complex of the rat respond to mechanical and chemical stimulation of the GI tract

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1998.274.2.g331 ◽

1998 ◽

Vol 274 (2) ◽

pp. G331-G341 ◽

Cited By ~ 10

Author(s):

Xueguo Zhang ◽

William E. Renehan ◽

Ronald Fogel

Keyword(s):

Acid Secretion ◽

Gastric Motility ◽

Extracellular Recording ◽

Chemical Stimulation ◽

Inhibitory Neurons ◽

Motor Nucleus ◽

Acid Solutions ◽

Gi Tract ◽

Dorsal Motor Nucleus ◽

Stimulation Of

Perfusing the duodenum with acid solutions dramatically reduces gastric motility and acid secretion. We propose that the presence of acid in the proximal small intestine initiates a vagovagal reflex that excites inhibitory neurons in the nucleus of the solitary tract (NST) and reduces the activity of the neurons in the dorsal motor nucleus of the vagus nerve (DMNV). However, results from several investigations suggest that the relevant circuit may not be as simple as we had believed. The present study was designed to address this dilemma by employing intracellular and extracellular recording and intracellular labeling techniques to provide direct information on the activity of neurons in the NST and DMNV during and after intestinal exposure to acid solutions. The results obtained prove that NST and DMNV neurons respond to HCl in the duodenum. In some instances, these neurons were very stimulus specific, although the majority of the cells in our sample (47% of NST neurons and 86% of DMNV neurons) also responded to distension of the stomach and/or duodenum. It is important to note, however, that many of the more broadly responsive neurons in the dorsal vagal complex were able to distinguish between mechanical and chemical stimulation of the gastrointestinal (GI) tract. Most of the NST neurons that responded to duodenal perfusion with HCl were excited by this stimulus. Conversely, activity of most of the DMNV neurons decreased after the onset of the HCl stimulus. These findings verify the existence of a vagovagal reflex pathway initiated by duodenal perfusion with acid. Presumably, this reflex would decrease gastric motility and acid secretion, reducing the amount of acid that enters the duodenum and ultimately protecting the intestinal mucosa.

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GABA signaling in the nucleus tractus solitarius sets the level of activity in dorsal motor nucleus of the vagus cholinergic neurons in the vagovagal circuit

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90504.2008 ◽

2009 ◽

Vol 296 (1) ◽

pp. G101-G111 ◽

Cited By ~ 29

Author(s):

Melissa A. Herman ◽

Maureen T. Cruz ◽

Niaz Sahibzada ◽

Joseph Verbalis ◽

Richard A. Gillis

Keyword(s):

Gastric Motility ◽

Kynurenic Acid ◽

Nucleus Tractus Solitarius ◽

Afferent Nerve ◽

Projection Neurons ◽

Motor Nucleus ◽

Nerve Terminals ◽

Receptor Blockade ◽

Dorsal Motor Nucleus ◽

Vagal Afferent

It has been proposed that there is an “apparent monosynaptic” connection between gastric vagal afferent nerve terminals and inhibitory projection neurons in the nucleus tractus solitarius (NTS) and that two efferent parallel pathways from the dorsal motor nucleus of the vagus (DMV) influence peripheral organs associated with these reflexes ( 6 ). The purpose of our study was to verify the validity of these views as they relate to basal control of gastric motility. To test the validity of a direct connection of vagal afferent terminals (known to release l-glutamate) directly impacting second-order projection neurons, we evaluated the effect of GABAA receptor blockade in the area of the medial subnucleus of the tractus solitarius (mNTS) on gastric motility. Microinjection of bicuculline methiodide into the mNTS produced robust decreases in gastric motility (−1.6 ± 0.2 mmHg, P < 0.05, n = 23), which were prevented by cervical vagotomy and by pretreatment with kynurenic acid microinjected into the mNTS. Kynurenic acid per se had no effect on gastric motility. However, after GABAA receptor blockade in the mNTS, kynurenic acid produced a robust increase in gastric motility. To test for the contribution of two parallel efferent DMV pathways, we assessed the effect of either intravenous atropine methylbromide or NG-nitro-l-arginine methyl ester on baseline motility and on decreases in gastric motility induced by GABAA receptor blockade in the mNTS. Only atropine methylbromide altered baseline motility and prevented the effects of GABAA receptor blockade on gastric motility. Our data demonstrate the presence of intra-NTS GABAergic signaling between the vagal afferent nerve terminals and inhibitory projection neurons in the NTS and that the cholinergic-cholinergic excitatory pathway comprises the functionally relevant efferent arm of the vagovagal circuit.

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Sex differences in GABAergic neurotransmission to rat DMV neurons

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00112.2019 ◽

2019 ◽

Vol 317 (4) ◽

pp. G476-G483 ◽

Cited By ~ 3

Author(s):

Yanyan Jiang ◽

Tanja Babic ◽

R. Alberto Travagli

Keyword(s):

Gastric Motility ◽

Functional Gastrointestinal Disorders ◽

Gonadal Hormones ◽

Female Rats ◽

Gastrointestinal Disorders ◽

Motor Nucleus ◽

Estrus Cycle ◽

Gastric Tone ◽

Gabaergic Neurotransmission ◽

Dorsal Motor Nucleus

Functional gastrointestinal disorders, including delayed gastric emptying and decreased gastric motility, are more prevalent in women, suggesting a potential role for circulating gonadal hormones, including estrogen. Gastric motility is tuned by the vagal inputs arising from the dorsal motor nucleus of the vagus (DMV), which is itself controlled by tonic GABAergic inputs. Estrogen increases GABA functions in various central nervous system areas; however, the effect of the estrus cycle in modulating GABAergic inputs onto DMV neurons, hence vagal control of gastric motility, has not been investigated. The aim of the present study was to test the hypothesis that GABAergic tone to DMV neurons, hence the vagal output to the stomach, varies according to sex and the estrus cycle. Experiments were performed on age-matched Sprague-Dawley male and virgin female rats; females were subdivided according to the high-estrogen (HE) or low-estrogen (LE) period of their cycle. Whole-cell patch-clamp recordings were made from gastric-projecting DMV neurons, and the response to perfusion with the GABAA receptor antagonist bicuculline was examined. The response of corpus and antrum tone and motility to bicuculline microinjected in the dorsal vagal complex, recorded via strain gauges sewn to the anterior gastric surface, was also assessed. Bicuculline increased the firing rate of DMV neurons, as well as gastric tone and motility, to a larger extent in HE compared with LE or male rats, suggesting a higher GABAergic tone in HE female rats. Taken together, the data support the hypothesis that GABAergic tone to DMV neurons varies according to sex and estrus cycle. NEW & NOTEWORTHY GABAergic neurotransmission to the dorsal motor nucleus of the vagus (DMV) plays a pivotal role in the modulation of gastric tone and motility. Gastric motility is reduced in women and may contribute to the higher incidence of functional gastrointestinal disorders. In the present study, we report that GABAergic tone to rat DMV neurons, hence vagal output to the stomach, varies according to sex and estrus cycle, and the GABAergic tone is increased during the high-estrogen period of the estrus cycle.

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Glucose does not activate nonadrenergic, noncholinergic inhibitory neurons in the rat stomach

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00561.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. R742-R750 ◽

Cited By ~ 16

Author(s):

Min Shi ◽

Allison R. Jones ◽

Manuel Ferreira ◽

Niaz Sahibzada ◽

Richard A. Gillis ◽

...

Keyword(s):

Gastric Motility ◽

No Reduction ◽

Cholinergic Neurons ◽

Inhibitory Neurons ◽

Motor Nucleus ◽

Dorsal Motor Nucleus ◽

The Central Nervous System ◽

Fos Expression ◽

Oxide Synthase

We reported previously that intravenously administered d-glucose acts in the central nervous system to inhibit gastric motility induced by hypoglycemia in anesthetized rats. The purpose of this study was to determine whether this effect is due to inhibition of dorsal motor nucleus of the vagus (DMV) cholinergic motoneurons, which synapse with postganglionic cholinergic neurons, or to excitation of DMV cholinergic neurons, which synapse with postganglionic nonadrenergic, noncholinergic (NANC) neurons, particularly nitrergic neurons. Three approaches were employed: 1) assessment of the efficacy of d-glucose-induced inhibition of gastric motility in hypoglycemic rats with and without inhibition of nitric oxide synthase [10 mg/kg iv nitro-l-arginine methyl ester (l-NAME)], 2) assessment of the efficacy of intravenous bethanechol (30 μg·kg−1·min−1) to stimulate gastric motility in hypoglycemic rats during the time of d-glucose-induced inhibition of gastric motility, and 3) determination of c-Fos expression in DMV neurons after intravenous d-glucose was administered to normoglycemic rats. Results obtained demonstrated that l-NAME treatment had no effect on d-glucose-induced inhibition of gastric motility; there was no reduction in the efficacy of intravenous bethanechol to increase gastric motility, and c-Fos expression was not induced by d-glucose in DMV neurons that project to the stomach. These findings indicate that excitation of DMV cholinergic motoneurons that synapse with postganglionic NANC neurons is not a significant contributing component of d-glucose-induced inhibition of gastric motility.

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GABAB Receptor Signaling in the Dorsal Motor Nucleus of the Vagus Stimulates Gastric Motility via a Cholinergic Pathway

Frontiers in Neuroscience ◽

10.3389/fnins.2019.00967 ◽

2019 ◽

Vol 13 ◽

Author(s):

Maureen T. Cruz ◽

Ghazaul Dezfuli ◽

Erin C. Murphy ◽

Stefano Vicini ◽

Niaz Sahibzada ◽

...

Keyword(s):

Gastric Motility ◽

Gabab Receptor ◽

Motor Nucleus ◽

Receptor Signaling ◽

Dorsal Motor Nucleus ◽

Cholinergic Pathway

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Localization of sites within dorsal motor nucleus of vagus that affect gastric motility

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1985.249.1.g73 ◽

1985 ◽

Vol 249 (1) ◽

pp. G73-G84 ◽

Cited By ~ 6

Author(s):

F. D. Pagani ◽

W. P. Norman ◽

D. K. Kasbekar ◽

R. A. Gillis

Keyword(s):

Heart Rate ◽

Electrical Stimulation ◽

Arterial Pressure ◽

Gastric Motility ◽

Motor Nucleus ◽

Fast Blue ◽

Medial Nucleus ◽

Dorsal Motor Nucleus ◽

Propantheline Bromide ◽

Stimulation Of

The purpose of our study was to determine the localization of sites within the dorsal motor nucleus of the vagus (DMV) of the cat that when stimulated would increase gastric motility. To do this, two types of experiments were performed. First, the retrograde tracer fast blue was injected into the antrum and pylorus, and labeled neurons in the DMV were identified. Second, electrical stimulation was performed in areas of the DMV labeled with fast blue as well as in nearby areas with no labeling while monitoring gastric motility, arterial pressure, and heart rate. Results from the first type of studies revealed that peak labeling in the DMV occurred between 0.56 and 1.56 mm rostral to obex. Electrical stimulation in this area using 100 microA, 0.2 ms duration pulses, and 50 Hz resulted in increases in antral and pyloric contractions in 20 animals. The magnitude of pyloric and antral responses elicited by stimulation of the DMV generally correlated to the number of cell bodies labeled with fast blue within the DMV. No changes in arterial pressure occurred, and only a slight (-4%) decrease in heart rate was observed. Maximal increases in motility occurred with 20 Hz (antrum) or 100 Hz (pylorus). These increases in motility were maintained even at 200- and 400-Hz stimulation. Ipsilateral vagotomy or pretreatment with propantheline bromide prevented the increases in gastric motility produced by electrical stimulation of the DMV. Electrical stimulation of more rostral sites in the DMV, the medial nucleus of the solitary tract (NTS), and an area within 1.0 mm medial to the DMV resulted in attenuated or no motility responses. Stimulation of the medial nucleus of the NTS did result in pronounced slowing in heart rate (-61 +/- 21 beats/min). These results suggest that there is a localization of a “stomach area” within the DMV and that electrical stimulation of this area results in gastric motility responses that are mediated by vagal fibers projecting directly to the stomach. In addition, electrical stimulation of the DMV results in selective effects on the gastrointestinal tract in that no pronounced changes in heart rate and arterial pressure occur.

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