1 Division of Basic Medical Sciences, Faculty of Medicine, and 2 School of Pharmacy, Memorial University of Newfoundland, St. John's, Newfoundland, Canada A1B 3V6
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ABSTRACT |
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The volume dependence of balloon distension-evoked esophageal rhythmic motor responses and their neural correlates was investigated in 72 urethane-anesthetized rats. With increasing balloon volume (75-200 µl), distal esophageal rhythmic contractions decreased in rate and became tonic in the range of 150-250 µl. This change in motor pattern involved only the striated musculature of the esophageal body and persisted after acute transection of the spinal cord at C2. Impulse frequency in single vagal afferents of the distal esophagus increased with intraluminal pressure over the entire range of balloon volumes tested (50-300 µl). Distension-responsive neurons in the nucleus tractus solitarii showed rhythmic burst activity (type I), tonic excitation (type II), or inhibition followed by off bursts (type III). Increasing strength of stimulation changed type I responses to nonrhythmic but intensified type II and III responses. We conclude that load-dependent changes in distal esophagus motility pattern are encoded by vagal afferents alone and do not involve a spinal afferent input even at near-noxious stimulus strengths.
esophagus; nucleus tractus solitarii; nucleus ambiguus; visceral pain
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INTRODUCTION |
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IN MAMMALS, SUCH AS THE RAT, peristaltic transport of food or drink through the esophagus relies chiefly on the full-length striated muscle coat of the tunica muscularis propria and, by inference, a neural control system made up of vagovagal reflex loops and brain stem interneurons (for reviews, see Refs. 6 and 26). In the distal portion of the rat esophageal body, reflex motility is characterized by rhythmic contractions evident during sustained balloon distension in the 20- to 100-µl range. This motor pattern is effected by a bilateral uncrossed reflex arc and is strongly facilitated by reafferent feedback (20). Stimulation of mechanosensory vagal endings of the rat esophagus elicits not only special visceral motor but also autonomic cardiovascular responses (19). The latter increase in magnitude with inflation pressure (19) beyond the range in which secondary peristalsis is elicited (21). Thus vagal mechanosensory input from the rat esophagus appears to encode information over a wide dynamic range. As yet, functional information on these primary vagal afferents is rather limited (2, 10), in particular as regards the properties of mechanosensory fibers supplying the distal esophagus. However, recent studies in the opossum have reported that esophageal vagal tension receptors possess a low threshold and low saturation pressure (27), whereas esophageal mechanosensory receptors innervated by dorsal root ganglionic (spinal or "sympathetic") afferents have either a wide dynamic range or high threshold (28).
In exploratory experiments, we noted that the reflex contraction pattern of the distal esophageal body changes from rhythmic to tonic as balloon distension is applied at increasing volumes. This observation led us to ask whether the altered motor pattern was caused by other sensory inputs from the esophagus, specifically the spinal afferent pathway, which is believed to mediate nociceptive signals (9, 17). Furthermore, it appeared necessary to examine the involvement of the esophageal smooth muscle tunica muscularis mucosae (TMM), as the latter receives its major sensory innervation via spinal afferents (16).
The present study was undertaken to examine the hypothesis that the vagal afferent input alone determines the pattern and force of distal esophageal contractions. Our specific aims were 1) to characterize the motor response patterns evoked by distal esophageal distension at volumes exceeding physiological levels (17, 29); 2) to examine the contribution of the TMM; 3) to determine the range in which vagal afferents from the esophagus encode intraluminal pressure signals; 4) to examine the role of spinal afferent input; and 5) to demonstrate alterations in neuronal activity patterns recorded at the level of the medulla oblongata.
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MATERIALS AND METHODS |
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All procedures in this study were approved by the Animal Care Committee of Memorial University of Newfoundland in accordance with the Guidelines of the Canadian Council on Animal Care.
General procedures. The experiments were performed in 72 male Sprague-Dawley rats (300-400 g) anesthetized with urethane (1.2 g/kg) given intraperitoneally. After tracheal intubation, the right carotid artery was cannulated for monitoring arterial blood pressure. Rectal temperature was maintained at 37-38°C by means of radiant heat.
A collapsible, high-compliance balloon made from PE-60 polyethylene tubing was filled with water and placed in the distal part of esophagus (11-12 cm from upper incisors) for distending the esophagus and simultaneous recording of intraluminal pressure. When fully distended, the oval-shaped balloon had a long and a short diameter of 15 and 9 mm, respectively, and a volume of 550 µl. As confirmed by autopsy, the center of the balloon was positioned in the diaphragmatic portion of the esophagus. Inflation of the balloon with 300 µl distended the esophagus to a cylindrical shape with an outer diameter of 6 mm and a length of 13 mm. In four experiments, the balloon was inserted into the gastroesophageal junction, and autopsy showed the tip of the balloon to protrude into the stomach. The balloon was connected to a manually operated syringe and an infusion pump (model 355, Sage Instruments), permitting graded or constant-rate incremental distension to be applied. Deflation was done manually, and the volume withdrawn was controlled closely to maintain a constant baseline. As shown in Fig. 1, the high compliance of this system enabled changes in intraesophageal pressure to be detected at sensitivity level of 1 mmHg.
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Drugs. Scopolamine methyl bromide (methscopolamine), nifedipine, and urethane were obtained from Sigma Chemical; tubocurarine chloride was purchased from Burroughs-Wellcome. All the drugs were administered intravenously in aqueous solution, except for nifedipine, which was dissolved in ethanol.
Data analysis.
To ensure reproducibility of responses, distensions at low volume and
volumes over 200 µl were applied at 3- to 5-min and at 0.5- to 1-h
intervals, respectively. In the case of rhythmic contractions,
intraluminal pressure was taken at the peak of each wave and averaged.
When rhythmic activity was evoked by constant-rate incremental
distension, the instantaneous frequency of contractions was calculated
from the reciprocal of the interval between two successive waves and
expressed as the number of waves per second (Hz). Neuronal discharge
rate was counted in spikes per second (Hz). Data are presented as
means ± SE, except where noted otherwise. Student's paired
t-tests were done with statistical software (Microcal Origin, Microcal Software). Differences were considered statistically significant at P < 0.05. Numbers (n) given
in parenthesis refer to individual separate experiments and, in the
case of extracellular unit recordings, to the total number of
individual units. In preparing Fig.
2B, data
files were imported into Microcal Origin, where digital subtraction of
pressure signals could be performed.
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RESULTS |
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Volume dependence of distal esophageal motility pattern. Distension produced both rhythmic and tonic pressure responses that varied with balloon volume and required an intact vagal innervation (Fig. 2). During constant-rate incremental distension, rhythmic contraction waves appeared at a threshold volume of 46.4 ± 2.7 µl (n = 9); they remained steady below 100 µl, slowed progressively between 100 and 200 µl, and were replaced by a tonic contraction between 150 and 250 µl (Fig. 2, B and C). A single-step distension in the range of 150-200 µl evoked an initial slow or tonic contraction that changed to rhythmic contraction waves as the intraluminal mean pressure declined gradually (Fig. 2A and see Fig. 6). Distension at volumes above 250 µl caused a persistent increase in reflex threshold, as evidenced by an increase in the minimal balloon volume required to elicit rhythmic activity (61.0 ± 2.7 µl, n = 9). Repeated testing at a volume of 300 µl demonstrated that the peak pressure evoked by subsequent distension declined by 22% and remained depressed for up to 2 h.
Placement of the balloon in the gastroesophageal junction revealed a modified response profile during constant-rate incremental distension (Fig. 2D). When the balloon volume reached 250-300 µl, intraluminal pressure appeared to level off, indicative of an increase in esophageal compliance. Bilateral vagotomy abolished this apparent relaxation response, along with rhythmic pressure wave activity preceding it (n = 4) (Fig. 2D). Ventral medullary units (n = 31) responding to distal esophageal distension were recorded in 17 rats. All units were silent at rest and did not fire unless a distension-evoked pressure wave occurred. The mean latency between the beginning of esophageal distension and the first evoked spike was 1.06 ± 0.07 s. The pattern of evoked spike activity depended on the magnitude of balloon inflation. At balloon volumes of 50-100 µl, rhythmic activity prevailed and consisted of spike bursts associated with the rising phase of each pressure wave (Fig. 2E). The mean spike frequency of the initial burst was 29.3 ± 2.2 Hz. Three units (9.6%) had a short burst discharge 1 ± 0.5 s after rapid deflation of the balloon. Responses to 200 µl were obtained in 19 units. Evoked firing was continuous during distension (3.0 ± 0.1 s) at a mean frequency of 34.4 ± 3.4 Hz and was temporally correlated with a nonrhythmic pressure rise in the distal esophagus (Fig. 2E). About two-thirds of the units (68.4%) showed a burst discharge 0.7 ± 0.2 s with balloon deflation.Differentiation of striated and smooth muscle components.
Acute blockade with methscopolamine (0.2 µmol/kg iv) of
parasympathetic cholinergic efferents to the TMM smooth muscle tunic (5) did not result in a measurable change in the amplitude and pattern of distension-evoked esophageal responses (Fig.
3A). During neuromuscular
paralysis with tubocurarine (0.15 µmol/kg iv), both rhythmic and
tonic contractions were completely inhibited for 10 min, and the
pressure-volume relationship was indistinguishable from that obtained
after vagotomy (not illustrated). In vagotomized rats, esophageal
compliance increased significantly at distension volumes 250 µl.
This apparent increase in compliance was augmented by nifedipine (0.8 µmol/kg iv), as evidenced by a further reduction in intraluminal
pressure high-volume distension (Fig. 3B).
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Spinal afferent component.
The intraluminal pressure responses to constant-rate incremental
esophageal distension were tested immediately (1-14 min) after
acute spinal cord transection at the level of C2
(n = 4). Distension evoked distal esophageal
contractions with a pattern identical to that obtained 1-10 min
before the spinal cord transection (Fig.
4). The responses remained stable for at
least 14 min after spinal cord transection. Before and after spinal
transection, the respective threshold volumes of rhythmic contractions
were 55.0 ± 9.7 and 54.2 ± 9.4 µl (P > 0.05). Tonic contractions appeared at ~200 µl. Thoracic
or diaphragmatic respiratory movements were absent when the respiratory
pump was temporarily turned off.
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Recordings in vagal esophageal afferents.
Vagal fibers (n = 140) were recorded in 18 rats. The
majority (n = 92) had a respiratory rhythmic discharge,
whereas the rest fired tonically (n = 41) or had a
cardiac rhythm (n = 7). Ten fibers (7 from left and 3 from right vagal trunk) that had been identified as single units and
responded to distal esophageal balloon distension were chosen for this
study. All of these afferents fired tonically at rest, without any
evidence of cardiac or respiratory modulation. The resting discharge
rate varied from 0.4 to 34 Hz (mean 9.7 ± 2.8 Hz). During distal
esophageal distension, the firing frequency increased and remained
elevated until the balloon was deflated. With deflation, a silent
period ensued before spontaneous activity resumed (Fig.
5, A and B). Firing
frequency increased linearly with the logarithm of esophageal inflation
pressure in the test range and did not show saturation even at balloon
volumes as large as 300 µl. As suggested by the rate of resting and
distension-evoked discharge, these fibers appeared to fall into three
subgroups (Fig. 5C). When impulse frequencies obtained at
300 µl were arbitrarily set as the maximum, the fractional increase
in firing frequency as a function of applied pressure showed a similar
slope in all the fibers tested (Fig. 5D).
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Volume dependence of dorsal medullary neuronal activities.
Sixty-seven units that responded to distal esophageal distension were
recorded in the intermediate and caudal NTS region. These unit
discharges corresponded to the three types described previously
(13), in terms their spontaneous background activity, firing patterns, and responses to balloon inflation or
deflation (Table 1). Average depths below
the extraventricular surface of the NTS for type I, II, and III units
were 471.6 ± 38.9 (SD), 460.0 ± 44.9, and 482.3 ± 43.0 µm (P > 0.05), respectively. Within a given track, type I units were separated by as little as 10-30 µm from type II and III units.
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Esophageal distension evoked rise in blood pressure. Distal esophageal distension was accompanied by a measurable arterial pressor response at every balloon volume tested. At 50-100 µl, systolic and diastolic pressure increased by 7.2 ± 0.9 and 8.9 ± 0.9 mmHg, respectively. At 200 µl, the respective increases were 12.6 ± 1.4 and 14.6 ± 1.4 mmHg. The volume dependence of the pressor response was statistically significant (P < 0.05).
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DISCUSSION |
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In the rat esophagus, motor control of the striated muscle tunica propria involves segmental vagovagal reflex circuits composed of primary vagal afferents, esophageal premotoneurons in the NTSc, and esophageal motoneurons in the nucleus ambiguus compact formation (1, 4, 6, 7, 11, 20, 31). As demonstrated in the present study, brain stem esophagomotor control entails the generation of different motility patterns. Thus the distal esophagus executes rhythmic or sustained (tonic) contractions depending on the level of afferent impulse activity. Our data not only confirm vagal input as the principal determinant in esophageal motor pattern control but also militate against a direct involvement of spinal afferent input. This idea agrees with previous work by Renehan et al. (24) showing that after vagotomy rat NTS neurons do not respond to intestinal distension, although neurons in the dorsal motor nucleus of the vagus (DMV) continue to do so through a spinal afferent pathway. As discussed below, the volume dependence of esophageal motor patterns and their central neuronal correlates need to be considered in relation to the dynamic range of vagal afferent input from the esophagus.
Volume dependence of distal esophagomotor pattern.
Both amplitude and pattern of distal esophageal contractions were found
to depend on the volume of the intraluminal balloon and, hence, the
magnitude of sensory input. The pressure-volume relationship obtained
would be expected to result from the interplay of four factors: reflex
contraction of the striated muscle tunica muscularis propria,
neurogenic or myogenic tension of the smooth muscle TMM, neurogenic
inhibition in the TMM, and the passive viscoelastic properties of both
muscle tunics. Because muscarinic acetylcholine receptor blockade
failed to change distension-evoked esophageal motility responses at
methscopolamine doses likely to suppress vagal efferent transmission in
the TMM, any centrally mediated reflex contraction of the TMM was
evidently too small to be detected. Accordingly, the active neurogenic
component of the intraluminal pressure change could be attributed to
the muscularis propria, a conclusion corroborated by the complete loss
of this response seen after vagotomy or curarization. At large balloon volumes (250 µl), a local myogenic contraction of the TMM occurred, as inferred from the decrease in intraluminal pressure induced by
nifedipine, a blocker of smooth muscle L-type calcium channels (30). The active neurogenic component attained peak
amplitude at balloon volumes between 150 and 200 µl.
Dynamic range of vagal afferents. To date, very few studies have dealt with esophageal vagal afferents in the rat (2, 10), and information concerning the activity elicited at high intraluminal pressures is lacking. In this study, single-fiber recording of vagal afferents revealed that all units sampled had a wide dynamic range. Thus, at balloon volumes of 250-300 µl, the firing frequency continued to increase, whereas the active vagovagal component of the evoked intraluminal pressure rise appeared to decrease. Because unilateral damage to the vagal innervation of the esophagus impairs rhythmic reflex peristalsis (20), we were unable to record the vagal afferent activity during reflex-evoked esophageal rhythmic contraction. Our findings differ from those reported in the opossum, in which esophageal vagal afferents were shown to have both a low threshold and low saturation pressure and, hence, to encode information only in the low pressure range (27).
Responsivity of NTS interneurons. As reported before (13), single-unit recordings in the NTSc area revealed three different neuron groups that responded to distal esophageal distension. Although these units were obtained in a narrowly restricted region, the ventralmost recording sites in some tracks may have encroached on the DMV. However, the firing pattern of the neurons concerned is clearly different from that of units recorded in the DMV that respond to esophageal distension (25). These DMV units were shown to fall into two types and to be activated or inhibited by esophageal distension (25). In the present work, although type III units showed a burst discharge and superficially resembled the excitatory DMV units, the burst discharge of our type III units occurred well after deflating the esophagus, whereas excitatory DMV units displayed a burst discharge before deflation of the esophagus. During high-volume distension, our type I units changed their firing pattern from rhythmic bursting to a tonic discharge, type II units were further activated, and type III units fell silent but rebounded with enhanced deflation bursts. These results demonstrate that the pattern and strength of NTSc interneuron activity are dependent on the level of vagal afferent input. Because the type I units and esophageal motoneurons had corresponding firing patterns over the entire pressure range tested, and because both reflected the motility pattern recorded in the esophagus, the present results corroborate our previous inference that the type I unit represents a premotoneuron (13). The functions of type II and type III units are currently not clear; however, it is reasonable to believe some of type II units represent interneurons mediating esophageal distal inhibition (13) or esophageal cardiovascular reflex responses (19). Recordings in the rat NTSc described by others (25) have shown that most units are silent at rest and do not fire rhythmically during esophageal distension. This discrepancy could be attributable to differences in the depth of anesthesia; moreover, in the rat thoracic esophagus, distension may evoke a single phasic motor response (20).
In summary, the evidence obtained in the present study suggests that the reflex motor response pattern and contractile force in the rat esophagus vary with the strength of vagal afferent input. The role, if any, of spinal afferent input in esophageal motor control is yet to be defined. The responsiveness of vagal afferent neurons and NTS interneurons to high-volume distension indicates that this system has the ability to encode information in a high-pressure, noxious range.Perspectives
Anatomically, vagal afferent terminal endings are located in esophageal myenteric ganglia, whereas relatively sparse innervation is found in the muscularis mucosae or striated musculature (16, 18). Vagal afferent neurons innervating the distal esophagus have smaller cell bodies and less or no staining intensity for calretinin and calbindin than do neurons projecting to other parts of the esophagus (16, 18). Because the presence of the calcium-binding proteins in the terminal structures is a characteristic of low threshold and rapidly adapting sensors (15), vagal afferents from the distal esophagus must have other properties. According to our data, the majority of this fiber population innervates slowly adapting receptors. Furthermore, the observed distension-evoked firing frequencies were much lower than those reported for afferents supplying the cervical esophagus (2). Thus regional response patterns may differ significantly in esophageal vagal afferents.In the present and previous (14, 19) studies, the magnitude of arterial blood pressure responses correlated with esophageal intraluminal pressure, functionally implying the similarity in dynamic range of vagal afferents mediating esophageal cardiovascular and motility responses. This dynamic range agrees with that observed in vagal fiber recordings. Our previous work implies that different populations of rat esophageal afferents in the vagus mediate distension-evoked reflex motility and two types of cardiovascular responses (14). Furthermore, anatomic studies suggest that substance P exists in some esophageal vagal afferents in the rat (18). Because of the limited number of esophageal vagal afferent fibers from which successful recordings were obtained, we cannot as yet discern different populations clearly. However, our data suggest that, although all fibers showed an overlapping dynamic range, individual activity levels differed. Clearly, more work is needed to classify mechanosensory vagal afferents of the rat esophagus in functional terms.
By virtue of their wide dynamic range, rat esophageal vagal afferents may represent sensory neurons that have the ability to generate both normal motility-regulating and nociceptive signals depending on the intensity of stimulation (9). Esophageal distension in humans is known to evoke pain (12), and esophageal spasm and intense peristaltic contractions are considered to be painful (8). In humans, distension-evoked pain has been reported to wax during relaxation and to wane during contraction; invariably, however, isometric contraction on an incompressible balloon was noted to be painful (23). Accordingly, the slow wave tonic contractions in the rat esophageal body that result from high-volume distension by means of a water-filled incompressible balloon may be equivalent to a "pain spasm" (23). Although it is generally believed that esophageal pain is mediated by spinal afferents (8, 22), there is evidence implicating an involvement of vagal afferent pathways (3, 19, 29). The present work supports the idea that esophageal vagal afferents contribute to nociceptive processing.
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ACKNOWLEDGEMENTS |
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This work was supported by the Medical Research Council of Canada. H. Dong holds a graduate fellowship from the Memorial University of Newfoundland.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. Bieger, Div. of Basic Medical Sciences, Faculty of Medicine, Memorial Univ. of Newfoundland, St. John's, Newfoundland, Canada A1B 3V6 (E-mail: dbieger{at}mun.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 29 November 2000; accepted in final form 31 January 2001.
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