Distal and deglutitive inhibition in the rat esophagus: Role of inhibitory neurotransmission in the nucleus tractus solitarii  Haiheng Dong, Christopher W. Loomis, Detlef Bieger  Gastroenterology  Volume 118, Issue 2, Pages 328-336 (February 2000) DOI: 10.1016/S0016-5085(00)70215-0 Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 1 Distal inhibition in rat esophagus. Single extracellular spike activity (ESA) recorded in rostroventral medulla oblongata at level of rostral nucleus ambiguus. Note absence of baseline discharge at rest. (A) Rhythmic burst discharge and phase-locked pressure wave activity are elicited by distal esophageal (DE) distention (80 μL); (B) both responses are suppressed during concurrent distention (50 μL) of the midthoracic esophagus (TE). (C) After bilateral cervical vagotomy, esophagus is not responsive to distal or combined distal and midthoracic esophageal distention. Initial pressure wave results from rapid injection of fluid into balloon catheter. Return of pressure below zero level marks rapid withdrawal of fluid from balloon. Gastroenterology 2000 118, 328-336DOI: (10.1016/S0016-5085(00)70215-0) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 2 Firing patterns of 3 different types of units in the NTSc region. (A) Type I unit shows slow rhythmic bursting in phase with intraluminal pressure waves during distention of the distal esophagus and prominent inhibition during midthoracic inflation followed by rebound discharge not associated with detectable esophageal pressure change (see Results). During superimposed midthoracic inflation, distal inhibition is evident as indicated by cessation of both unit burst activity and pressure waves; note immediate return of both responses upon deflation of thoracic balloon. (B) Type II unit fires nonrhythmically during either thoracic or distal esophageal distention. Concurrent distention (right panel) augments unit discharge but simultaneously arrests rhythmic pressure wave activity in distal esophagus. (C) Type III (deflation) unit fires 1–2 spikes in phase with the falling phase of the esophageal pressure wave during distal inflation. During midthoracic inflation alone or combined with distal inflation, the unit falls silent. Balloon deflation at either level triggers single off discharge of similar strength; however, note longer latency of discharge with thoracic esophageal distention. Esophageal distention was performed at fixed balloon volumes (80 μL distal esophageal [DE]; 50 μL midthoracic esophagus [TE]). Initial sharp peak in pressure trace (*) is an experimental artifact caused by rapid injection of fluid into balloon catheter. Small pressure fluctuations are caused by respiration. Gastroenterology 2000 118, 328-336DOI: (10.1016/S0016-5085(00)70215-0) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 3 Effects of bicuculline, 2-(OH)-saclofen, and strychnine on distal inhibition. (A) Bilateral application of bicuculline to the extraventricular surface of NTS reversibly attenuates distal inhibition. (B) 2-(OH)-saclofen fails to alter distal inhibition. (C) After bilateral NTS surface application of strychnine, suppression of distal esophageal distention evoked rhythmic pressure wave activity during midthoracic balloon inflation is reversibly attenuated. Balloon inflation volumes: 80 μL in distal esophageal (DE), 50 μL in midthoracic esophagus (TE). Traces in A and B are from same animal, C from another animal. Pharyngeal pressures traces (not illustrated) remained inactive in all cases. Gastroenterology 2000 118, 328-336DOI: (10.1016/S0016-5085(00)70215-0) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 4 Deglutitive inhibition of distention-evoked esophageal activity. (A) Presumptive esophageal motoneuron responds with rhythmic bursts during distal esophageal inflation. Trace shown in the right panel shows a brief pause (down arrow) coincident with pharyngeal pressure (PP) wave, indicative of buccopharyngeal swallow. The pressure traces recorded in upper balloon (not illustrated) remain inactive. Note concomitant notch in rising phase of esophageal pressure wave. Local blockade of (B–D) GABA or (E) glycine receptors in the NTS fails to change deglutitive inhibition. The antagonists were applied bilaterally to the NTS surface. Doses refer to amount of drug applied to each side. (F) Intravenous application of picrotoxin also fails to block deglutitive inhibition. Traces in A; B, C, and E; and D and F are from 3 different animals, respectively. All responses were recorded 5 minutes after each drug application. Oblique arrows mark swallow-induced fast relaxation. Distal balloon distention was performed at a volume of 80 μL. Swallowing was evoked by intratracheal injection of 40% ethanol (2 μL) in trace A and gentle displacement of the pharyngeal balloon in traces B–F. Gastroenterology 2000 118, 328-336DOI: (10.1016/S0016-5085(00)70215-0) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 5 Schematic diagram outlining proposed mechanism for distal inhibition. The premotor neurons in the NTSc receive segmentally organized esophageal vagal afferent input and control the activity of motoneurons in the compact formation of nucleus ambiguus (AMBc) that innervate the striated muscle tunica muscularis propria (TMP) of the esophagus. Distal inhibition results from excitation of GABAergic and/or glycinergic interneurons in the NTSc (•) that are activated by collaterals (dotted lines) of either vagal afferent or esophageal premotor neurons controlling proximal esophageal segments. The inhibitory output of these putative local interneurons impinges on NTSc neurons controlling distal esophageal segments and is mediated by postsynaptic ligand-gated chloride channels. The system mediating deglutitive inhibition may involve a different type of NTSc interneuron and/or different sites of synaptic inhibition, e.g., primary afferent terminals, or motoneurons. NG, nodose ganglion. Gastroenterology 2000 118, 328-336DOI: (10.1016/S0016-5085(00)70215-0) Copyright © 2000 American Gastroenterological Association Terms and Conditions