Basic Characteristics of Glutamate and Umami Sensing in

the Oral Cavity and Gut

Reflex Effects of Oral, Gastrointestinal and Hepatoportal Glutamate

Sensors on Vagal Nerve Activity1
Akira Niijima
Niigata University School of Medicine, Niigata, Japan

KEY WORDS:
rats

monosodium L-glutamate

vagus nerve

Monosodium L-glutamate (MSG) is a popular food additive

that produces the umami taste (savory), which may be a
marker for protein-rich foods (just as sweetness is thought to
be the marker for carbohydrate-rich foods). Recently, we reported that umami taste stimulation activates the efferent
limbs of the gastric (Niijima 1991a), pancreatic and hepatic
branches of the vagus nerve (Niijima 1991b), in association
with an increase in insulin secretion (Niijima et al. 1990).
Jeannigros (1982) identified the existence of amino acid receptors in the duodenointestinal canal, using extracellular
recordings of afferent activity of vagal nodosal neurons. The
report described many receptors that were sensitive to arginine
and leucine, and others that were sensitive to glutamine. In
relation to the function of intestinal amino acid receptors,
Meyer et al. (1976) reported that continuous intraduodenal
infusion of amino acids stimulates pancreatic secretion in the
dog. Such results indicate that a reflex increase in efferent

stomach

pancreas

neurophysiology

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ABSTRACT Glutamate sensors in the oral cavity, gastrointestinal canal and hepatoportal region are thought to
function in the reflex regulation of vagal activity to the gastrointestinal tract and pancreas. In support of this notion,
the findings summarized in this report demonstrate that the infusion of monosodium glutamate (MSG) into the
stomach (150 mmol/L, 3 mL), duodenum (150 mmol/L, 3 mL) and portal vein (10 mmol/L, 0.1 mL) increases afferent
activity in the vagal gastric, celiac and hepatic nerves, suggesting the existence of glutamate sensors in the gastric
wall, intestinal wall and hepatoportal region. Further, oral, gastric and intestinal infusions of MSG (150 mmol/L,
isotonic solution) and the infusion of MSG (10 mmol/L, 0.1 mL) into the portal vein resulted in reflex activation of
the efferent gastric and pancreatic branches of the vagus. The intravenous injection of 10 mmol/L MSG (0.1 mL)
also induced a reflex activation of the efferent discharges of the gastric branch of the vagus; however, in hepatic
and celiac vagotomized rats, the intravenous injection of MSG (1 or 3mol/L, 1 mL) produced no effect on gastric
vagal activity. The results of these experiments demonstrate the importance of the afferent nerve signals from
visceral glutamate sensors in generating the reflex activation of gastrointestinal and pancreatic functions in
response to MSG administration. J. Nutr. 130: 971S973S, 2000.

activity has occurred in the pancreatic branch of the vagus.

Still other findings suggest that amino acid sensors exist in the
hepatoportal region; these sensors send signals through the
hepatic branch of the vagus nerve to the central nervous
system (Niijima and Meguid 1995). A reflex modulation of
autonomic outflow, originated by glutamate sensors in the
hepatoportal region, may thus exist. This paper continues an
examination of these issues, and considers primarily the reflex
effects of oral, gastric, intestinal and hepatoportal glutamate
sensor stimulation on vagal gastric and pancreatic nerve activity.
MATERIALS AND METHODS

Male Wistar rats (300 g) were acclimated to our animal facilities

for 1 wk before experimentation. During this time, they had free
access to food and water. They were anesthetized with urethane
(1g/kg, intraperitoneal), and tracheal cannulas were inserted. Under
a dissecting microscope, a nerve filament was dissected from the
peripheral cut end of the gastric, celiac or hepatic branch of the vagus
nerve to record afferent nerve activity via a pair of silver wire
electrodes. Efferent nerve activity was similarly recorded from a nerve
filament dissected from the central cut end of the gastric or pancreatic
branch of the vagus nerve (Niijima 1991a and 1991b, Niijima and
Meguid 1995). A rate meter with a reset time of 5 s was used to
observe the time course of nerve activity. Discharge rate is expressed
as means SEM (n 10). For taste stimulation, a solution of 150
mmol/L MSG (Ajinomoto, Tokyo) was applied to the tongue surface
for 10 min; the tongue was flushed with distilled water at the con-

1
Presented at the International Symposium on Glutamate, October 1214,
1998 at the Clinical Center for Rare Diseases Aldo e Cele Dacco, Mario Negri
Institute for Pharmacological Research, Bergamo, Italy. The symposium was
sponsored jointly by the Baylor College of Medicine, the Center for Nutrition at the
University of Pittsburgh School of Medicine, the Monell Chemical Senses Center,
the International Union of Food Science and Technology, and the Center for
Human Nutrition; financial support was provided by the International Glutamate
Technical Committee. The proceedings of the symposium are published as a
supplement to The Journal of Nutrition. Editors for the symposium publication
were John D. Fernstrom, the University of Pittsburgh School of Medicine, and
Silvio Garattini, the Mario Negri Institute for Pharmacological Research.

0022-3166/00 $3.00 2000 American Society for Nutritional Sciences.

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SUPPLEMENT

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clusion of each test session. For intestinal administration, 150

mmol/L MSG (3 mL) was infused through a catheter inserted into the
duodenum. The intraportal injection of 10 mmol/L MSG (0.1 mL)
was made through a small catheter inserted into the hepatic portal
vein.
The effect of taste stimulation, and of intragastric, intraduodenal
or intraportal infusion of MSG on nerve activity was determined by
comparing the mean number of spikes in 10 successive 5-s bins (see
above) before and at time points after application of the test stimulus.
Treatment effects were evaluated statistically using ANOVA and the
Scheffe test (P 0.05).

RESULTS
The effect of MSG administration to gastric, intestinal
and hepatoportal MSG sensors on vagal afferent activity).
In the upper three traces of Figure 1, the top trace shows an
example of the effect of MSG stimulation of the gastric wall on
afferent activity of the vagal gastric nerve fibers. After infusion
of the MSG solution (150 mmol/L, 3 mL), a long-lasting
increase in afferent activity was observed. The discharge rate
before and 30, 60 and 90 min after infusion was 59.2 3.3,
112.2 3.5*, 109.3 4.0* and 96.0 4.4* impulses/5 s,
respectively; the asterisk indicates a significant increase, compared with preinfusion value, P 0.05 (ANOVA, Scheffe

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FIGURE 1 Upper panel: the effect of monosodium glutamate

(MSG) administration on the afferent activities of vagal gastric, intestinal
and hepatoportal glutamate sensors. Lower panel: the effect of reflex
activation of vagal gastric and pancreatic nerve activity from oral,
gastric, intestinal and hepatoportal glutamate sensors. (Niijima, A.,
unpublished observations.)

test). The middle trace indicates an example of vagal celiac

afferents, which showed a clear increase after intraduodenal
infusion of MSG (150 mmol/L, 3 mL). The discharge rate just
before and 30, 60 and 90 min after infusion was 57.4 3.9,
137.6 5.0*, 112.0 3.3* and 96.6 3.9* impulses/5 s,
respectively. The bottom trace indicates the afferent activity
of the hepatic branch of the vagus nerve in response to an
injection of 10 mmol/L MSG (0.1 mL) into the portal vein.
The discharge rates before and after injection were 67.0 2.7,
76.7 2.2*, 92.5 2.5* and 88.5 2.1* impulses/5 s (same
time sequence as indicated above). A gradual and clear increase in discharge rate occurred.
Vagal efferent activity after MSG administration. Figure
1 (lower panel) presents the efferent vagal responses to the
stimulation of peripheral MSG sensors. As shown in the top
traces, taste stimulation by 150 mmol/L MSG for 10 min
clearly increased efferent activity of the vagal gastric and
pancreatic nerves. The efferent discharge rate in the vagal
gastric nerve before and 30, 60 and 90 min after taste stimulation was 73.8 3.8, 86.4 3.1*, 100.9 2.6* and 142.1
5.2* impulses/5 s, and that in the vagal pancreatic nerve was
63.7 2.2, 113.3 2.0*, 129.2 2.3* and 178.1 3.1*
impulses/5 s, respectively. The efferent discharge rates before
and 30, 60 and 90 min after intragastric MSG infusion on vagal
gastric and vagal pancreatic nerve activity were 60.0 2.6,
63.9 1.3, 72.2 1.8*, 82.8 2.9*, and 63.6 2.0, 70.6
2.3*, 87.1 2.3*, 98.2 2.1* impulses/5 s, respectively
(second trace from the top). The efferent discharge rates
before, and 30, 60 and 90 min after the intraduodenal infusion
of 150 mmol/L MSG solution (3 mL) were 61.8 1.5, 51.0
1.2, 87.7 1.8*, 96.7 2.6* impulses/5 s, respectively, in
the gastric vagus nerve, and 71.8 3.8, 77.7 2.0, 78.7
3.0, 82.8 4.1* impulses/5 s, respectively, in the vagal
pancreatic nerve (third trace from the top). The intraportal
injection of a small amount of an MSG solution (10 mmol/L,
0.1 mL) also increased efferent nerve activity in the gastric
and pancreatic branches of the vagus nerve. The discharge
rates before and 30, 60 and 90 min after intraportal injection
were 69.0 2.2, 96.8 3.0*, 117.2 2.9*, and 135.8 3.4*
impulses/5 s (vagal gastric efferents), and 63.4 1.3, 71.2
2.2*, 83.1 3.2*, and 79.9 2.6* impulses/5 s (vagal
pancreatic efferents), respectively (bottom traces).
The effect of an intravenous injection of MSG on gastric
vagal nerve activity. Figure 2 (upper panel) shows the effect
of an intravenous injection of an MSG solution on the efferent
activity of the gastric branch of the vagus nerve. As shown in
the top trace, an intravenous injection of 10 mmol/L MSG
solution (0.1 mL) produced a rise in the efferent activity of the
gastric branch of the vagus nerve. This activation could be
blocked by prior hepatic vagotomy, i.e., after sectioning of the
hepatic vagus branch, successive intravenous injections of 10
mmol/L, 100 mmol/L and 1 mol/L MSG (0.1 mL each) failed
to facilitate efferent nerve activity. Finally, the intravenous
injection of a large volume of a 1 mol/L MSG solution (1 mL)
resulted in a transient increase in nerve activity. The bottom
trace in Figure 2 shows the effect of an intravenous injection
of a large volume of a concentrated MSG solution (1mol/L or
3mol/L, 1 mL) on vagal gastric nerve activity in a hepatic,
gastric and celiac vagotomized rat. As shown in the trace,
these injections were without effect.
DISCUSSION
The umami (savory) taste is known to be independent of
the four classical, basic tastes (Ninomiya and Funakoshi 1987,
Schiffman and Gill 1987, Yamaguchi 1987, Yamamoto and

SENSORY SIGNALS FROM VISCERAL GLUTAMATE SENSOR

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LITERATURE CITED

FIGURE 2 Upper panel: the effect of an intravenous (iv) injection of

monosodium glutamate (MSG) on the efferent activity of the vagal
gastric nerve in normal and vagotomized rats. Lower panel: schematic
representation of the reflex pathway from visceral glutamate sensors to
gastric and pancreatic nerve. (Niijima, A., unpublished observations.)

Asai 1987). MSG stimulates oral glutamate sensors and produces the umami taste. Niijima et al. (1990) reported that
umami taste stimulation with MSG increased the efferent
activity of the vagal pancreatic nerve and stimulated insulin
secretion. Jeannigros (1982) also identified glutamine-sensitive receptors in the duodenointestinal canal using extracellular recordings of vagal nodosal neurons. Niijima and Meguid
(1995) subsequently reported the existence of amino acid
sensors in the hepatoportal region via recordings of afferent
signals from the hepatic branch of the vagus nerve. However,

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the occurrence of glutamate sensors in the hepatoportal region

has not been identified until now (these results). Further,
stimulation by MSG solutions of oral and intestinal glutamate
sensors enhanced efferent gastric vagus activity (Niijima
1991b).
Thus, the present experimental data demonstrate the existence of glutamate sensors not only in the oral cavity and
intestinal wall, but also in the gastric wall and hepatoportal
region, as well as a reflex activation of efferent discharges in
the vagal gastric and pancreatic nerve from oral, gastric, intestinal and hepatoportal glutamate sensors. Figure 2 (lower
panel) presents a schematic representation of the reflex pathway from gastric, intestinal and hepatoportal glutamate sensors
to vagal gastric and pancreatic outflow. Figure 2 (upper panel)
demonstrates that activation of gastric vagus activity by the
intravenous injection of MSG is partially blocked by sectioning the hepatic branch of the vagus nerve, whereas sectioning
of the hepatic, gastric and celiac branches of the vagus nerve
completely blocks the effects of intravenous MSG. This response suggests that the activation of vagal activity by MSG
administration is due mainly to an activation of peripheral
glutamate sensors, and not the direct stimulation of autonomic
centers within the brain.

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