1 Department of Physiology, The roles of
tachykinin neurokinin-1 (NK1)
receptors in the induction of fictive retching, hypersalivation, and
gastric responses associated with emesis induced by abdominal vagal
stimulation were studied in paralyzed, decerebrated dogs. Vagal
stimulation induced gradual increases in salivary secretion and
activity of the parasympathetic postganglionic fibers to the
submandibular gland, relaxation of the gastric corpus and antrum, and
fictive retching. However, hypersalivation and increased nerve activity were suppressed and antral contractility was enhanced during fictive retching. An NK1 receptor
antagonist, GR-205171, abolished the enhancement of antral
contractility and fictive retching but had no effect on corpus and
antral relaxation. Hypersalivation and increased nerve activity were
inhibited by GR-205171 but were not completely abolished. Reflex
salivation by lingual nerve stimulation was unaffected. These results
suggest that GR-205171 acts on the afferent pathway in the bulb and
diminishes hypersalivation and antral contraction related to emesis as
well as fictive retching but does not affect gastric relaxation or
hypersalivation induced by the vagovagal, vagosalivary, and
linguosalivary reflexes.
retching; substance P; chorda tympani; linguosalivary reflex
IT IS WELL KNOWN THAT abdominal vagal afferent nerves
play an important role in the induction of emesis by visceral
stimulation. 5-HT3 receptor
antagonists have been shown to suppress emesis by blocking the
stimulatory effects of the chemical and radiological treatment of
cancers on peripheral vagal nerve terminals (6, 7). Recently,
neurokinin-1 (NK1) receptors
have attracted a great deal of attention from many investigators,
because these receptors in the central nervous system are thought to be
involved in the induction of emesis (1, 11-13, 25-27, 29).
However, almost all of these studies have revealed the effects of
NK1 antagonists only on
somatomotor responses. Lang et al. (22) indicated that a series of
neural mechanisms is involved in emesis: the first participates in
gastrointestinal motor correlates, and the second induces somatomotor
emetic responses. Furukawa and Okada (9) reported that canine salivary
secretion was increased before fictive retching induced by emetic
stimuli but was suppressed during fictive retching. Because the
salivary center receives two opposite inputs in the preretching phase
and in the retching phase, these workers suggested the existence of an
afferent relay station for emesis that triggers the central pattern
generator (CPG) for somatomotor emetic action (3, 4, 21) and
simultaneously induces autonomic nervous responses associated with
emesis. Therefore, in further research on mechanisms of emesis, it is
necessary to investigate the effects of
NK1 antagonists on autonomic
nervous responses associated with emesis, as well as somatomotor
responses. However, there has been no previous study of the effects of
NK1 receptor antagonists on
autonomic nervous responses associated with emesis. This study was
undertaken to investigate the effects of
NK1 receptor antagonist on the
activity of the afferent relay station suggested by Furukawa and Okada
(9) by observing the effects on autonomic responses after emetic
stimulation.
Because salivary secretion from the submaxillary gland exactly
corresponds to the activity of the innervating nerves and because quantitative analysis is easy, we used salivary secretion as an index
of autonomic activity. Afferent stimulation of the vagus nerves is
thought to be useful for studying emesis in acute experiments in dogs,
because stable emetic responses can be induced repeatedly. Therefore,
afferent vagal stimulation was used to induce emesis. However, vagal
stimulation also induces other reflex responses. For example,
esophageal and gastric distension and afferent stimulation of the
gastric vagal branch elicit hypersalivation by the vagosalivary reflexes (9, 16, 19), and afferent stimulation of the gastric vagal
branch elicits gastric relaxation by the vagovagal reflex (18).
Salivary secretion is thought to be increased by vagal stimulation not
only related to emesis but also via the vagosalivary reflexes. Qu et
al. (23) reported that gastric antral contractility was inhibited by
vagal stimulation via the vagovagal reflex but enhanced during fictive
retching. Recording of gastric motility makes it possible to
distinguish between the gastric response related to emesis induced by
vagal stimulation and that evoked by the vagovagal reflex. For these
reasons, in this study we investigated the effects of a nonpeptide
NK1 receptor antagonist,
GR-205171, on fictive somatomotor responses, gastric corpus and antral
contractile responses, and salivary secretion associated with emesis
induced by vagal stimulation. Furthermore, the effects of GR-205171 on salivary responses associated with emesis were compared with those on
salivary secretion induced by the linguosalivary reflex (9, 15) to
examine its effects on the efferent pathway to the salivary glands.
Portions of the results have been reported elsewhere as an abstract
(8).
General methods of animal preparation.
All of the experiments were approved by the Animal Research Committee
of the Kawasaki Medical School and conducted according to the
Guide for the Care and Use of Laboratory
Animals. Six mongrel dogs (6-11 kg) were fasted
for 16 h and used for the present study. All of the dogs were
anesthetized with ketamine (25 mg/kg im). Almost all of the animals
became quite flaccid within 5 min. If the animal was not flaccid enough
~5 min after administration, a further 10 mg/kg of ketamine was
added. Midcollicular decerebration was performed during the subsequent
10 min. The dogs were paralyzed with gallamine triethiodide (2 mg/kg
iv) and artificially ventilated with a respirator. Body temperature was
maintained near 37.5°C by a feedback system, using an infrared
heating lamp. A microtip pressure transducer was inserted into the
right femoral artery, and mean systemic arterial pressure was monitored
using a digital pressure monitor (Camino, M 420). To record gastric
circular contractilities, two force transducers were sewn onto the wall
of the gastric corpus and antrum ~3 cm orad to the pyloric sphincter
in the direction of the circular muscle. A polyethylene catheter (2 mm
ID, 20 cm long) was inserted into the left Wharton's duct, and drops
of saliva (each drop was ~0.02 ml) from the catheter were counted using a photoelectric drop counter.
Recording of nerve discharges.
The left phrenic nerve and the nerve innervating the left rectus
abdominis were isolated through incisions along the cervical midline
and the dorsal edge of the obliquus externus abdominis, respectively.
The postganglionic branch from the right submandibular ganglion was
isolated after partial removal of the masseter muscle through a midline
maxillary incision. These nerves were carefully separated from the
surrounding connective tissues under a stereoscopic dissecting
microscope and covered with liquid paraffin. Centrifugal discharge from
these nerves was monitored via bipolar platinum wire electrodes.
Neural discharge was converted into frequency histograms of
200-ms, 500-ms, or 1-s bins using spike counters (Dia Medical,
DSE-325 A), and the histograms were recorded (NEC San-ei, OMNIACE
RT2116A-08). Activities of these nerves were monitored with an
oscilloscope (Nihon Kohden, VC 11). The details of these methods have
been reported previously (9).
Stimulation of the lingual and vagal nerves and experimental
design.
The lingual nerve on the left side was isolated, and electrical
afferent stimulation (1 ms, 10 V, 10 Hz) was applied via a bipolar
silver wire electrode to induce reflex salivation from the left
submaxillary gland. The dorsal vagal trunk was sectioned just above the
diaphragm, and fictive retching was induced by electrical stimulation
(1 ms, 20-25 V, 3-10 Hz) of the central part of the severed
vagal trunk. Coactivating rhythmic volleys of the phrenic nerve and the
nerve to the rectus abdominis were used as an index of fictive
retching. For the control experiments, vagal stimulation of at least 90 s was applied as emetic stimulation. When fictive retching persisted 90 s after the initiation of vagal stimulation, the stimulation was
discontinued after the cessation of fictive retching. In the control
experiments, two to four applications of vagal stimulation and two or
three applications of lingual nerve stimulation of a 15-s period were
applied. The NK1 receptor antagonist GR-205171
[2-methoxy-5-(5-trifluoromethyl-tetrazol-l-yl-benzyl)-(2S-phenyl-piperidin-3S-yl)-amine dihydrochloride] (Glaxo Wellcome) was then administered (50 µg/kg iv). This dose of 50 µg/kg was comparable to that (0.1 mg/kg) used in dogs by Gardner et al. (12) and was effective enough to
suppress fictive retching induced by vagal stimulation but did not
produce any obvious changes in resting respiratory activity of the
phrenic nerve or in blood pressure and heart rate in dogs. Five or ten
minutes after the administration of GR-205171, vagal stimulation was
again applied for a 110- to 140-s period and repeated two to four times
at 10-min intervals. Lingual nerve stimulation was applied two to three
times before or after vagal stimulation. Rest periods of more than 2 or
6 min were allowed after lingual and vagal nerve stimulation,
respectively.
Statistical analysis.
The volume of salivary secretion, frequency of spikes of converted
neural discharge of the parasympathetic nerve, and relative magnitudes
of gastric contraction were statistically analyzed. In one dog, stable
neural activity could not be obtained throughout the entire experiment,
so the statistical analysis of neural activity was performed in the
five remaining dogs. The analyses of salivary secretion and nerve
discharge were performed by considering 10-s periods. The changes in
salivary secretion induced by afferent vagal stimulation are thought to
be composed of two different responses, as mentioned above
(introduction), i.e., salivation related to emesis and salivation by
the vagovagal reflex. Because the latencies to the start of fictive
retching differed between individual dogs before GR-205171, and fictive
retching disappeared after GR-205171, the data before GR-205171 were
analyzed during the period from 70 s before to 160 s after the
initiation of fictive retching, and the data after GR-205171 were
analyzed during the period from 30 s before to 200 s after the
initiation of vagal stimulation. The basal values before stimulation
were determined by averaging the values obtained from 30 to 60 s before
stimulation. The mean frequency of nerve activity from 90 to 100 s and
the mean volumes of saliva from 120 to 130 s after the cessation of stimulation were also calculated. The values obtained from each dog
were averaged (n = 2-4). The mean
values obtained from all of the dogs were again averaged, and the
results were expressed as means ± SE
(n = number of dogs). The statistical
significance of differences between the basal value before stimulation
and the value of each 10-s period was analyzed by Student's
t-test (paired). Furthermore, to
compare the control responses in salivary secretion and parasympathetic
nerve activity before GR-205171 with the test responses after
GR-205171, the values during 10-s periods in the following three phases
as well as the two basal phases were also analyzed. Before GR-205171,
salivary secretion and nerve activity were gradually increased by vagal
stimulation, decreased during fictive retching, and again increased
after the cessation of retching. Therefore, the values of salivary
secretion and nerve activity in each 10-s period immediately before
fictive retching (preretching phase), immediately before the cessation of retching (late-retching phase), and immediately after the cessation of stimulation (postretching phase) in the control responses were compared with those at the corresponding times after the onset of vagal
stimulation in the test responses after GR-205171. The mean values of
the nerve activity from 40 to 50 s after the cessation of retching in
the controls, and those at the corresponding times in the test cases
after GR-205171, were also calculated to determine any difference in
the time course of recovery. The relative magnitudes of gastric
contraction were measured by calculating the area of the recorded
contractility within a 30-s period before stimulation and within a 30-s
period during the maximal antral contraction during fictive retching in
the control experiments. After the application of
NK1 antagonist, the area of the
recorded contractility was calculated within a 30-s period before
stimulation and within a 30-s period at the corresponding time as in
the control. The statistically significant differences between the
basal values before and ~10 min after the administration of
NK1 antagonist and the values
before and after stimulation in the corpus and antral contractilities
were analyzed. Probability values of P <0.05 were considered significant.
Effects of vagal stimulation on the parasympathetic nerve activity
to the submandibular gland, salivary secretion, and gastric motility in
the control experiments.
Vagal stimulation induced fictive retching, with a mean latency of 41.3 ± 7.2 s (n = 6) in all of the
dogs. Multiunit activity of the right chorda tympani nerve was slightly
increased by vagal stimulation, although high-frequency activity was
transiently exhibited at the onset of the vagal stimulation in some
cases. This increased activity gradually increased further until
fictive retching occurred. Subsequently, the excitatory effect was
partially depressed in association with retching and again recovered
after the cessation of retching. After the cessation of vagal
stimulation, nerve activity gradually decreased and returned to the
basal level ~1 min after the end of stimulation (Fig.
1A).
The mean 10-s values of the activity immediately before retching
(preretching phase) and immediately before (late-retching phase) and
after (postretching phase) the cessation of retching and at 40-50
s after the cessation of retching were significantly larger than the
basal value. There was no significant difference between the basal
value and the value at 90-100 s after the cessation of retching
(Fig. 2). Similar changes were observed in
salivary secretion from the contralateral submandibular gland, although
these changes were delayed by several seconds from the changes in nerve
activity (Fig. 1A). The mean 10-s
volumes at the preretching, late-retching, and postretching phases were
significantly greater than the basal value. The mean volume at
120-130 s after the cessation of retching was not significantly different from the basal value before stimulation (Fig.
3).
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Fig. 1.
Effects of a neurokinin-1 (NK1)
receptor antagonist, GR-205171, on salivary secretion and activity of
parasympathetic nerve innervating the submandibular gland induced by
emetic vagal stimulation. A: before
administration of GR-205171 (control).
B: after administration of GR-205171
(50 µg/kg iv). In B, vagal
stimulation was applied 30 min after administration of
GR-205171. Phrenic N., centrifugal activity of the phrenic
nerve represented as frequency histograms with 200-ms bins; Abdominal
M. N., centrifugal activity of an abdominal muscle branch of the
L1 spinal nerve represented as
frequency histograms with 200-ms bins; Saliva from L. Mand., salivary
flow (1 drop was considered to be 0.02 ml) from the left submandibular
gland; R. Parasympa. N., centrifugal activity of the parasympathetic
nerve innervating the right submandibular gland represented as
frequency histograms with 500-ms bins; imp, impulses; stim,
stimulation. After GR-205171, fictive retching was not induced by vagal
stimulation, and responses in salivary secretion and nerve activity
were decreased but sustained. Note that salivary secretion during
retching in the control experiments was equivalent to that induced by
vagal stimulation after GR-205171.
View larger version (43K):
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Fig. 2.
Changes in activity of parasympathetic nerve innervating the
submandibular gland associated with emetic vagal stimulation before and
after GR-205171. A: before GR-205171.
B: after GR-205171 (50 µg/kg).
C: comparison of responses in nerve
activity before and after GR-205171.
y-Axis, mean frequency of nerve
activity in a 10-s period. Basal, mean values determined by averaging
values obtained from 30 to 60 s before stimulation; 90-100 s after
Off, mean values in 10-s period from 90 to 100 s after cessation of
vagal stimulation; N, number of
animals. In A and
B, numbers in parentheses indicate
total number of stimulations. In A,
horizontal bar at top indicates
duration of retching. Numbers above bar indicate number of incidences
of retching sustained at corresponding time/total number of
stimulations. In B, horizontal bar at
top indicates duration of stimulation.
Numbers above bar indicate number of stimulations applied at
corresponding time/total number of stimulations. In
C, Pre-Retch shows mean values during
10-s periods immediately before retching in control responses and at
corresponding time after onset of stimulation after
GR-205171. Late-retch, mean frequencies during 10-s periods
immediately before cessation of retching in control and at
corresponding time after GR-205171; Post-Retch, mean values during 10-s
periods immediately after cessation of retching in control and at
corresponding time after GR-205171; 40-50 s after Off,
mean values in 10-s period from 40 to 50 s after cessation of vagal
stimulation. * P < 0.05, ** P < 0.01 vs. basal values.
@ P < 0.05, @@ P < 0.01 before vs. after GR-205171. NO, no significant difference
(P > 0.05).
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Fig. 3.
Changes in salivary secretion associated with emetic vagal stimulation
and salivary response to lingual nerve stimulation before and after
GR-205171. A: before GR-205171.
B: after GR-205171 (50 µg/kg).
C: comparison of salivary responses to
vagal stimulation before and after GR-205171.
D: comparison of salivary responses to
lingual nerve stimulation before and after GR-205171. C and
D: crosshatched bars, before GR-205171. Hatched bars, after
GR-205171. y-Axis shows mean volume of
salivary secretion in a 10-s period. N., nerve. For further details,
see legend to Fig. 2. * P < 0.05, ** P < 0.01 vs. basal
values.
@ P < 0.05 before vs. after GR-205171.
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Effects of vagal stimulation on activity in the parasympathetic nerve innervating the submandibular gland and salivary secretion after GR-205171. After the intravenous administration of 50 µg/kg of GR-205171, no fictive retching was induced in any of the dogs, although facilitatory effects on the phrenic and abdominal muscle nerves activities were sometimes observed (Fig. 4B). Vagal stimulation induced a small, but sustained, increase in parasympathetic nerve activity and salivary secretion, and the responses rapidly diminished after the cessation of stimulation (Fig. 2B). The mean values of salivary secretion and nerve activity during vagal stimulation after GR-205171 were similar to those during the retching phase in the control experiments (Figs. 2 and 3C, late retch). All of the mean 10-s values during and just after vagal stimulation (preretch, late retch, and postretch) were significantly higher than the basal value, but the facilitation in nerve activity at 40-50 s after the cessation of stimulation observed before GR-205171 was abolished. The mean 10-s value of nerve activity after GR-205171 was significantly decreased at the postretching phase and at 40-50 s after the cessation of stimulation compared with the control experiment but was not significantly changed in the preretching and late-retching phases (Fig. 2C). Similar changes were observed in salivary secretion, although these were delayed after the changes in nerve activity by several seconds (Fig. 3B). The mean 10-s value of salivary secretion after GR-205171 was significantly decreased in the preretch and postretch phases compared with that in the control experiment but was not significantly changed in the late-retch phase or at 120-130 s after the cessation of stimulation (Fig. 2C). To summarize, after GR-205171, salivary secretion was increased by vagal stimulation, but the marked increases in the preretching and postretching phases observed in the control experiments were diminished, and a small increase of the same magnitude as that observed during fictive retching in the control experiments was sustained.
Effects of vagal stimulation on gastric motility after GR-205171. GR-205171 did not change basal gastric contractilities. The mean relative magnitudes of gastric contractility in the 30-s periods just before and ~10 min after GR-205171 were 4.31 ± 0.39 and 4.02 ± 0.41 in the corpus and 4.33 ± 0.48 and 4.20 ± 0.55 in the antrum, respectively. There was no significant difference between the basal values before and after GR-205171. After GR-205171, antral contractility was slightly inhibited by vagal stimulation in five dogs (Fig. 4B) and was not changed in the remaining dog. The significant increase in the mean value of antral contractility during fictive retching observed in the control experiments was abolished by GR-205171 (Fig. 5). The mean value of the relative magnitude of antral contractility in the 30-s period just after vagal stimulation was significantly decreased to 3.81 ± 0.52 from the basal value of 4.05 ± 0.55. Corpus contractility was immediately inhibited by vagal stimulation in all six dogs (Fig. 4B). A significant decrease in the mean value of the relative magnitude of corpus contractility during fictive retching persisted even after GR-205171 (Fig. 5).
Salivary secretion induced by lingual nerve stimulation before and after GR-205171. Salivary secretion was significantly increased by afferent stimulation of the lingual nerve (10 V, 10 Hz) in the control experiments (Fig. 3D). The salivary response to lingual nerve stimulation was not significantly changed by GR-205171. Salivary secretion was also significantly increased by lingual nerve stimulation after GR-205171. There were no significant differences in the basal values or in the stimulation response values before or after GR-205171 (Fig. 3D).
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DISCUSSION |
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Salivary and gastric responses induced by vagal stimulation. Previously, Furukawa and Okada (9) reported in chloralose-anesthetized dogs that salivary secretion and the activity of the parasympathetic nerve innervating the submandibular gland were facilitated before fictive retching induced by intravenous apomorphine or intragastric copper sulfate and were suppressed during retching. In the present study, similar results were obtained by vagal stimulation in decerebrated dogs, although small increases in salivary secretion and nerve activity still remained during retching. It was suggested in a previous study that an afferent relay station in the bulb that drives the CPG for the somatomotor emetic act (3, 4, 21) may simultaneously excite the salivary secretory center, and outputs from the CPG may inhibit the salivary secretory center as well as elicit somatomotor responses (Fig. 6). The difference in the degree of inhibition during retching is thought to be due to the different methods used to induce retching. Vagal stimulation elicits the vagosalivary reflex to a greater extent than intravenous apomorphine, so, in the present study, inhibitory outputs from the CPG might suppress the excitatory effects from the relay station relating to emesis, but not the vagosalivary reflex.
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Effects of NK1 antagonist on somatomotor emetic acts induced by vagal stimulation. The selective nonpeptide NK1 receptor antagonist GR-205171 abolished fictive retching in all of the dogs in the present study. GR-205171 and other nonpeptide and peptide NK1 receptor antagonists, e.g., CP-99,994, GR-203040, and GR-82334, have been shown to inhibit somatomotor emetic responses induced by various stimuli, i.e., afferent vagal stimulation, cisplatin, and copper sulfate, in the ferret, dog, and Suncus murinus (1, 11-13, 25-27). Therefore, it is clear that NK1 receptors play an important role in the induction of somatomotor emetic responses by various stimuli.
Effects of an NK1 antagonist on changes in gastric contractility induced by vagal stimulation. In the present study, GR-205171 abolished the excitatory response in the antrum as well as fictive retching, whereas the inhibitory responses in the corpus and antrum remained unaffected. Because the excitatory response and inhibitory responses are thought to be related to emesis and the vagovagal reflex, respectively, as mentioned above, GR-205171 may suppress not only retching activity but also the accompanying phenomena associated with emesis, without inhibiting other physiological reflexes. Similar results obtained for salivary secretion seem to support this hypothesis, as mentioned below.
Effects of an NK1 antagonist on changes in salivary secretion induced by vagal stimulation. In the control experiments, salivary secretion and the activity of the parasympathetic nerve innervating the submandibular gland were greatly increased before retching (preretching phase) and immediately after the cessation of retching (postretching phase). After GR-205171, salivary secretion at the corresponding times as in the control was significantly reduced, whereas the mean value during the retching phase (late-retching phase) in the control was equivalent to that at the corresponding time after the NK1 antagonist. We previously reported that the frequency of parasympathetic nerve activity was related to the volume of salivary secretion (9). In the present study, the difference between the discharge rates before and after GR-205171 in the preretch phase was not significant. However, this seems to be due to the large variation in discharge rate among the individual dogs. Because the salivary secretion in the preretching phase was significantly decreased after GR-205171, parasympathetic nerve activity may also be decreased by GR-205171. It has been reported that substance P induces salivary secretion in the rat and ferret (2, 30), and Giuliani et al. (14) reported that a selective NK1 receptor agonist stimulated rat salivary secretion more potently than substance P itself. In the present study, however, salivary secretion induced by lingual nerve stimulation was not significantly different before and after GR-205171. Therefore, GR-205171 seems to have little or no effect on the efferent pathway of the salivary response induced by emetic stimulation under our experimental conditions in dogs. Because salivary secretion and parasympathetic nerve activity were strongly suppressed during retching induced by apomorphine (9), as mentioned above, the following conclusions should be considered. 1) The increased response in salivary secretion and nerve activity in the control experiments may reflect the sum of the response to the vagosalivary reflex and that related to emesis. 2) During the retching phase in the control experiments, only the response to the vagosalivary reflex may be present. 3) GR-205171 may diminish only the response related to emesis but leave the response to the vagosalivary reflex unaltered, which appeared immediately after the initiation of vagal stimulation with constant magnitude.
Possible location of NK1 receptors, and schema of the central mechanisms for induction of the salivary and gastric responses related to emesis. Gardner et al. (11) reported that a peptide NK1 receptor antagonist, GR-82334, inhibited cisplatin-induced emesis in the ferret after hindbrain administration but not when given peripherally. It has been shown that some vagal C fibers contain immunoreactive substance P (28) and are sensitive to capsaicin (10, 17). Koga and Fukuda (20) suggested that the medial part of the nucleus of the solitary tract (NTS) mediates emetic signals via the abdominal vagus to the CPG. Recently, Shiroshita et al. (24) reported in dogs that capsaicin or resinferatoxin, an ultrapotent capsaicin analog, administered into the fourth ventricle abolished fictive retching induced by vagal afferent stimulation but did not abolish the retching induced by stimulation of the medial NTS. These results suggested that substance P from capsaicin-sensitive vagal afferent nerves mediates visceral emetic signals to the medial NTS. However, very recently, Fukuda et al. (5) suggested that microinjection of GR-205171 at the medullar area medial to the most rostral part of the nucleus ambiguus not only abolished fictive retching but also decreased hypersalivation before retching. This area is situated between the medial NTS and the CPG, which may exist in the area dorsal to the retrofacial nucleus (3, 21). Therefore, it seems that vagal afferent fibers that mediate emetic signals are capsaicin sensitive, but the relevant transmitter may not be substance P, although further studies are required to clarify the transmitter from the vagal afferent fibers.
On the basis of the results of the present study and previous work, the following conclusions are postulated (Fig. 6). 1) Emetic vagal afferent nerves excite the neurons in the NTS, but NK1 receptors may not play a major role in this excitation. 2) The outputs from the neurons in the NTS excite an afferent relay station that drives the CPG and simultaneously facilitates salivary secretion and antral contractility. 3) NK1 receptors may exist on the neurons in the relay station. 4) The outputs from the CPG inhibit the salivary secretory centers and elicit somatomotor responses. This inhibition may be induced via the relay station. In conclusion, an NK1 receptor antagonist may abolish salivary and gastric responses related to emesis as well as fictive retching but does not change the responses induced by the linguosalivary reflex and vagovagal gastric reflexes. ![]() |
ACKNOWLEDGEMENTS |
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We thank Dr. Kiyoko Fukai for help with the statistical analysis and Kiwamu Aoki and Rie Ohtomo for their assistance with the quantitative analysis.
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FOOTNOTES |
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This study was supported in part by a Research Project Grant (no. 9-711) from Kawasaki Medical School.
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. §1734 solely to indicate this fact.
Address reprint requests to N. Furukawa.
Received 8 April 1998; accepted in final form 15 July 1998.
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