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Central Neurocircuitry Associated with Emesis
Pamela J. Hornby, PhD
Ingestion of toxin, traumatic events, adverse drug
reactions, and motion can all result in nausea and
emesis. In addition, cyclic vomiting syndrome is
quite prevalent in the pediatric population. Coordina-
tion of the various autonomic changes associated
with emesis occurs at the level of the medulla oblon-
gata of the hindbrain. Chemosensitive receptors de-
tect emetic agents in the blood and relay this infor-
mation by means of neurons in the area postrema to
the adjacent nucleus tractus solitarius (NTS). Ab-
dominal vagal afferents that detect intestinal luminal
contents and gastric tone also terminate in the NTS
(gelatinosus, commissural, and medial subnuclei).
The NTS is viscerotopically organized into subnuclei
that subserve diverse functions related to swallow-
ing (subnucleus centralis), gastric sensation (subnu-
cleus gelatinosus), laryngeal and pharyngeal sensa-
tion (intermediate and interstitial NTS), baroreceptor
function (medial NTS), and respiration (ventrolateral
NTS). Neurons from the NTS project to a central
pattern generator (CPG), which coordinates the se-
quence of behaviors during emesis, as well as di-
rectly to diverse populations of neurons in the ventral
medulla and hypothalamus. Thus, it is critical to re-
alize that there is not an isolated “vomiting center,”
but rather groups of loosely organized neurons
throughout the medulla that may be activated in se-
quence by a CPG.
The newer antiemetic agents appear to block re-
ceptors in the peripheral endings of vagal afferents
to reduce “perception” of emetic stimuli and/or act in
the dorsal vagal complex. A primary site of action of
5-HT
3
-receptor antagonists is by means of the vagal
afferents. Neurokinin-1 receptor (NK
1
R) antagonists
are antiemetics, because they act at a site in the
dorsal vagal complex. Part of their effectiveness may
be the result of inhibition of the NK
1
R on vagal motor
neurons to prevent fundic relaxation, which is a pro-
dromal event essential for emesis. Delta
9
-tetrahy-
drocannabinol (⌬
9
-THC), the major psychoactive
component of marijuana, can be therapeutically use-
ful as an antiemetic. The site of action of ⌬
9
-THC is
on cannabinoid CB1 receptors in the dorsal vagal
complex. However, it decreases fundic tone and an-
tral motility. It is not easy to predict the potential
antiemetic effects of drugs that alter motility. Al-
though antiemetic drugs are available for manage-
ment of acute chemotherapeutic-induced emesis,
few treatments are effective for delayed emesis or
cyclic vomiting syndrome. Am J Med. 2001;111(8A):
106S–112S. © 2001 by Excerpta Medica, Inc.
Ingestion of toxin, “cephalic” responses to traumatic
or repugnant events, and motion can result in nausea
and emesis. For many patients, treatment with opioid
analgesics, anticancer agents, and other drugs also may
cause nausea and emesis. In addition, cyclic vomiting
syndrome (CVS) is present in approximately 2% of the
pediatric population.
1
CVS is characterized by episodes
of frequent and intractable vomiting followed by symp-
tom-free periods that vary in duration.
Nausea cannot be studied in nonhumans, although be-
haviors such as excessive salivation and swallowing pro-
vide insight into the neural control of this unpleasant
sensation. On the other hand, vomiting that comprises
retching and expulsion phases can easily be studied in
experimental models. Because emesis occurs infre-
quently, toxins such as apomorphine, anticancer agents,
or irradiation can be used to study neural control of these
complex events. During the retching phase, muscles of
the diaphragm and abdomen simultaneously contract or
relax. During expulsion, there is prolonged contraction
of the abdominal muscles that is coordinated with the
activity of the intercostal muscles and the muscles of the
larynx and pharynx. The glottis is closed and the soft pal-
ate elevated. In the intestines, a retrograde giant contrac-
tion occurs and the gastric fundus relaxes, which is an
essential prodromal event for emesis.
2
Pulse rate and
breathing increase and sweating occurs.
HINDBRAIN NEUROCIRCUITRY
ASSOCIATED WITH EMESIS
Coordination of this extraordinary combination of auto-
nomic changes occurs at the level of the medulla oblon-
gata of the hindbrain (Figure 1). The region that is essen-
tial for coordinating these behaviors is located between
the level of the obex (opening of central canal into fourth
ventricle) to the level of the rostral portion (compact
zone) of the nucleus ambiguus, which is termed the ret-
rofacial nucleus in cats (Figure 2).
3–5
Thus, output neu-
rons that control the muscles involved in emesis are scat-
tered throughout the medulla oblongata. What is distinc-
tive about vomiting is that these neurons must be
From the Department of Pharmacology and Neuroscience Center of
Excellence, Louisiana State University Health Sciences Center, New Or-
leans, Louisiana, USA.
This work was supported by the National Institute of Diabetes and
Digestive and Kidney Diseases (Grant No. PHS 42714).
Requests for reprints should be addressed to Pamela J. Hornby, PhD,
Department of Pharmacology, Louisiana State University Health Sci-
ences Center, 1901 Perdido Street, New Orleans, Louisiana 70112.
106S © 2001 by Excerpta Medica, Inc. 0002-9343/01/$20.00
All rights reserved. PII S0002-9343(01)00849-X
activated in the appropriate sequence. This sequence of
events can best be understood in terms of a “pattern gen-
erator,”rather than a “vomiting center”per se.
It is beyond the scope of this brief overview to describe
all of the neurons that coordinate control of the dia-
phragm, inspiration, blood pressure, heart rate, larynx,
pharynx, tongue, lower esophageal sphincter (LES), and
gastric fundus. In addition, a considerable body of litera-
ture already describes the neural circuitry underlying re-
spiratory and abdominal pressure changes associated
with emesis.
6
Therefore, this article will focus on neural
control of upper gastrointestinal changes and possible
sites of action of antiemetic drugs. It should become ap-
parent that considerable overlap exists in the neurons
that control emesis and those involved in other supra-
esophageal functions, such as swallowing. Gaps in our
knowledge include, for example, information on how the
brain and enteric nervous system coordinate the giant
retrograde contraction that extends through the intes-
tines to the level of the gastric corpus.
2,7
Wang and Borison
8
first proposed the idea of a vomit-
ing center. However, some of their original observations
have not been supported by more recent studies. For ex-
ample, they showed that vomiting could be induced by
stimulation of the dorsolateral medulla in cats,
8
but other
investigators have been unable to find a discrete site from
which they could consistently elicit vomiting.
9
Moreover,
vomiting could still be induced after neuronal cell bodies
in the dorsomedial medulla were selectively lesioned.
10
Thus, the simple concept of a vomiting center that could
be readily manipulated pharmacologically or surgically
has not been upheld.
What has been upheld by subsequent research, how-
ever, is the original observation that the integrity of the
abdominal vagus is essential for emesis.
11
In ferrets, stim-
ulation of mucosal chemoreceptors in the stomach or
duodenum by luminal hydrochloride or hypertonic sa-
line results in long latency and sudden increases in vagal
efferent discharge associated with the prodrome of vom-
iting.
12
Thus, signals associated with luminal contents are
detected by vagal afferent chemoreceptors in the mucosa
and relayed to the hindbrain by a rapid and distinctive
firing pattern from vagal motor nerve fibers. Interest-
ingly, successful treatment of intractable epilepsy in pa-
tients has been accomplished by repeated stimulation of
the left vagus nerve through implanted electrodes, but
nausea and vomiting do not occur with this treatment.
13
Thus, vagal activation alone is not sufficient to trigger
emesis.
The other idea proposed by earlier studies that has
passed the test of time is that a major site involved in
triggering emesis is near the area postrema. Chemorecep-
tors in the area postrema, which are outside of the blood–
brain barrier, are sensitive to circulating emetic agents,
such as apomorphine or cytotoxic drugs.
14
An example of
how these peripheral chemoreceptors are involved in
triggering emesis comes from observation of patients
with Parkinson’s disease who receive L-dopa. Emesis
caused by dopamine receptor stimulation is less likely
when L-dopa is coadministered with a peripherally acting
dopa decarboxylase inhibitor. Thus, peripherally active
dopamine, converted from L-dopa, triggers emesis. In
contrast to drug-induced emesis, the area postrema is less
Figure 1. Some triggering factors in emesis that impinge on the emetic circuitry in the hindbrain medulla from the level of the
medullary–spinal transition to the pons.
A Symposium: Central Nervous System Emetic Circuitry/Hornby
December 3, 2001 THE AMERICAN JOURNAL OF MEDICINE威Volume 111 (8A) 107S
involved in motion sickness,
15
which is caused by stimu-
lation of labyrinthine end organs.
Some of the hindbrain neurocircuitry of neuronal
populations controlling behaviors related to emesis are
shown in Figure 2. Activation of gastric vagal afferents
stimulates neurons in the area postrema
16
and in the
nearby nucleus tractus solitarius (NTS), specifically in the
subnucleus gelatinosus neurons.
17
In this subnucleus of
the NTS, there is a marked concentration of gastric affer-
ent input. Emetic agents activate a similar distribution of
neurons in the NTS of cats
3
and ferrets.
18
Different stud-
ies have either reported the presence or absence of c-fos
activation in the subnucleus gelatinosus after emetic or
abdominal stimuli, although this partly may be caused by
the paucity of neurons in this subnucleus, which is pre-
dominantly composed of axodendritic synapses related
to gastric reflexes.
19
Neurons activated in the dorsal vagal
complex (DVC), in addition to the subnucleus gelatino-
sus, are located in areas controlling swallowing (subnu-
cleus centralis of the NTS), baroreceptor reflexes (medial
NTS), respiration (ventrolateral NTS), and tone/motility
of the stomach and LES (dorsal motor nucleus of the
vagus). Recently, we have shown that approximately half
of the preganglionic motor neurons in the dorsal motor
nucleus of the vagus that innervate the LES also innervate
the gastric fundus.
20
This may have relevance for emesis,
as both fundic relaxation and LES relaxation precede
emesis.
7
Widespread areas of activated cells are also noted in the
ventral medulla after emetic stimuli (Figure 2). These re-
gions include premotor neurons in the compact zone of
the nucleus ambiguus (retrofacial nucleus) that innervate
the larynx and pharynx; para-ambigual expiratory-re-
lated neurons that control respiration; ventrolateral med-
ullary neurons that control sympathetic outflow to main-
tain blood pressure; and parasympathetic neurons in the
nucleus ambiguus that innervate the heart. Projections
from the NTS to the ventrolateral medulla may be partic-
Figure 2. Approximate location of neurons in hindbrain medulla controlling behavior during emesis. Only neuronal structures
and regions in which there is increased c-fos activation after an emetic stimulus in decerebrate cats are labeled. To schematically
represent the data, locations of labeled regions may not be anatomically precise. Lines indicate primary function of areas activated;
for simplicity, neural connections involved are not shown. (Inset) enlargement of the dorsal vagal complex (DVC) illustrating that
abdominal vagal afferents terminate in the gelatinosus and medial nucleus tractus solitarius (NTS) subnuclei as well as in the more
caudal commisural NTS (lower right). Information from vagal afferents and the area postrema is transferred to the NTS, where the
subnuclei illustrated subserve diverse functions (as described elsewhere in this supplement
4,5
). This information is also relayed to
neurons in the central pattern generator (CPG) and surrounding regions. Neurons controlling respiratory behavior are located in the
Bo¨tzinger/ventral respiratory group (Bo¨t/VRG). Premotor neurons controlling the larynx and pharynx are located in the nearby
rostral nucleus ambiguus/retrofacial nucleus (nAmb/RFN). Changes in neurohypophyseal hormone release from the hypothalamus
are relayed from catecholaminergic groups in the ventrolateral medulla (R/CVLM) and from the NTS. Blood pressure and heart rate
are controlled by the R/CVLM and nAmb, respectively. Extensive connections between the NTS and dorsal motor nucleus (DMN)
of the vagus control motor function of the lower esophageal sphincter (LES) and stomach. AP ⫽area postrema; cen ⫽subnucleus
centralis; com ⫽commissural subnucleus of NTS; gel ⫽subnucleus gelatinosus; int ⫽intermediate subnucleus; is ⫽interstitial
subnucleus; med ⫽medial NTS; mlf ⫽medial longitudinal fasciculus; OXY/AVP ⫽oxytocin/arginine vasopressin; R/CVLM ⫽
rostral/caudal ventrolateral medulla; RM ⫽raphe magus; TS ⫽tractus solitarius; V4 ⫽fourth ventricle; vl ⫽ventrolateral subnu-
cleus of NTS; X11 ⫽hypoglassal nucleus. (Modified with permission from J Neurosci.
3
)
A Symposium: Central Nervous System Emetic Circuitry/Hornby
108S December 3, 2001 THE AMERICAN JOURNAL OF MEDICINE威Volume 111 (8A)
ularly important for mediating the respiratory motor
components of vomiting.
21,22
Neurons in the rostral por-
tion of the nucleus ambiguus (at the level just caudal to
the facial nucleus, hence termed retrofacial nucleus in
cats) have firing characteristics consistent with a possible
role as central pattern generators.
23,24
Vasopressin and oxytocin levels increase in humans
experiencing nausea from both illusory self-motion and a
number of emetic-producing treatments. Dopamine an-
tagonists abolish both nausea and the increase in vaso-
pressin.
25
A vasopressin V1 antagonist has demonstrated
complete blockade of emesis and other significant symp-
toms in squirrel monkeys.
15
In contrast to vasopressin,
oxytocin release in the hypothalamus can be triggered by
normal eating and can signal sensations of both satiety
and malaise behavior in rats.
26
Discharge firing of oxyto-
cin neurons, but not vasopressin neurons, accompanies
gastric distention and cholecystokinin administration.
27
The pathway by which this occurs can be directly from
the NTS to the magnocellular hypothalamic neurons, and
by means of catecholaminergic neurons in the ventrolat-
eral medulla (Figure 2). These are identified as part of the
central pathway by which afferent abdominal vagal stim-
ulation increases plasma vasopressin and also increases
arterial pressure.
28
Overall, as Verbalis et al
26
have con-
cluded, increasing levels of neurohypophyseal hormones
are a marker of a disinclination to eat, with higher levels
indicating malaise rather than satiety.
Expulsion has relatively little to do with gastrointesti-
nal function; rather, it is a response to changes in intra-
abdominal and intrathoracic pressure generated by the
respiratory muscles. The respiratory-related components
of fictive vomiting can be abolished by lesions of the lat-
eral medulla at the level of the retrofacial nucleus, where
respiratory premotor and motor neurons exist.
10
Phrenic
motor neurons controlling the diaphragm are largely
confined to the C5–C7 levels of spinal cord location. In-
puts to these neurons during inspiratory behaviors
unique to emesis arise not only from premotor neurons
in the ventral medulla nucleus ambiguus region, but also
from neurons in the midline of the medulla.
29
SITE OF ACTION OF NEWER
ANTIEMETIC DRUGS
It is becoming clear that the vagal afferents are a major
site of action of antiemetic drugs (Figure 3). The anti-
emetic action of the 5-HT
3
-receptor antagonists, such as
granisetron and odansetron, are primarily the result of
Figure 3. Selected drugs that affect emesis and their site(s) of action (if known).
␣
2
R⫽adrenergic
␣
2
-receptor; CPG ⫽central
pattern generator; D
2
R⫽dopamine
2
-receptor; ⌬
9
-THC ⫽⌬
9
-tetrahydrocannabinol; DVC ⫽dorsal vagal complex; 5-HT ⫽
serotonin; H ⫽histamine; mR ⫽cholinergic muscarinic receptor; NK ⫽neurokinin; R ⫽receptor.
A Symposium: Central Nervous System Emetic Circuitry/Hornby
December 3, 2001 THE AMERICAN JOURNAL OF MEDICINE威Volume 111 (8A) 109S
their effects on the abdominal vagal afferents.
30
This is
because cytotoxic agents increase the release of 5-HT
from enterochromaffin cells in the small intestinal mu-
cosa, and 5-HT subsequently activates 5-HT
3
receptors
on vagal abdominal afferents.
31,32
The discharge of affer-
ent vagal fibers to 5-HT is completely abolished by
5-HT
3
-receptor antagonists.
33
However, these agents are
less effective in delayed vomiting. Hasler
34
also has re-
viewed data suggesting that 5-HT
4
agonists may amelio-
rate nausea in patients with gastroparesis and functional
dyspepsia because of prokinetic effects that stimulate gas-
tric emptying.
It is assumed that some underlying causes of vomiting
result from impaired gastrointestinal motor activity.
Disruption of gastric slow-wave dysrhythmias (resulting
in both tachygastria and bradygastria) has been associ-
ated with nausea and emesis related to motion sick-
ness
35
and pregnancy hyperemesis.
36
Neurokinin-1 re-
ceptor (NK
1
R) antagonists have been shown to prevent
emesis in many species, including humans,
37
and show
promise in treating delayed chemotherapy-evoked eme-
sis. Furthermore, animal studies have indicated a broad
spectrum of action for NK
1
R antagonists in treating di-
verse causes of nausea and vomiting.
38
The antiemetic
properties of NK
1
R antagonists are thought to act in the
DVC,
39–41
but the specific site of action is not known.
They may act in the area postrema, because HSP-117 and
CP-99,994 (NK
1
R antagonists) applied to the area pos-
trema have been shown to decrease expulsion and retch-
ing episodes induced by morphine and copper sulfate.
42
However, in these particular studies, diffusion of the
drugs may have affected other regions of the DVC. It is
unlikely that NK
1
R antagonists prevent emesis at the level
of the primary afferent inputs to the NTS because intra-
venous GR-205171 does not affect the response of medial
NTS neurons to vagal stimulation even though retching
was abolished.
43
We have recently shown that the NK
1
Ris
highly expressed in vagal motor neurons
44
and NK
1
Rac
-
tivation in this region potently evokes gastric fundic re-
laxation.
45
Because fundic relaxation is a prodromal
event essential for emesis, it is attractive to speculate that
these antagonists inhibit fundic relaxation by blocking
the NK
1
R on preganglionic neurons in the dorsal motor
nucleus of the vagus. In summary, the antiemetic site of
action of NK
1
R antagonists in the DVC is elusive but may
involve vagal motor neurons that control fundic relax-
ation.
The major psychoactive component of marijuana, ⌬
9
-
tetrahydrocannabinol (⌬
9
-THC), inhibits gastrointesti-
nal transit.
46
It is also used as an antiemetic
47
and syn-
thetic cannabinoids dronabinol and nabilone have been
produced for this use. Delta
9
-THC inhibits gastric emp-
tying in humans,
48
and we found that in rats ⌬
9
-THC
administered peripherally decreased fundic tone and an-
tral motility by means of cannabinoid CB1 receptors.
49
This effect is completely abolished by vagotomy and,
when the drug is applied to the surface of the medulla
above the DVC, at a dose that is ineffective when given
intravenously, it decreases fundic tone and antral motil-
ity.
49
Cannabinoid receptor mRNA is located in the DVC
of the rat,
50
and therefore ⌬
9
-THC may act partly in the
DVC to decrease fundic tone. This may be helpful to al-
low the stomach to accommodate food intake, which is
a problem for patients with functional dyspepsia, but it is
an enigma how ⌬
9
-THC–evoked gastrointestinal stasis
and fundic relaxation may contribute to its antiemetic
effects.
Cyclic Vomiting Syndrome
The cause of CVS is incompletely understood. Its onset is
generally in children younger than 5 years of age and
results in approximately 12 attacks per year. In some
cases, it ceases with adolescence.
1
CVS may be related to
migraine headaches. Some success has been noted with
use of the antimigraine drug sumatriptan (a 5-HT
1D
ag-
onist) to reduce the severity of cyclic vomiting attacks.
38
Paradoxically, sumatriptan is not as effective for migraine
in children as it is in adults.
51,52
Vomiting may be stress
initiated, and patients try to avoid the trigger for their
attacks.
CONCLUSIONS
The locations of neurons that coordinate the bodily func-
tions associated with emesis are spread throughout the
medulla, supporting the notion that a central pattern
generator coordinates the sequence of behaviors during
emesis. This region receives indirect input from both the
area postrema and abdominal vagus by means of the
NTS. Despite this information, there is little evidence that
antiemetic agents act directly on the central pattern gen-
erator. Neither is there any indication that drugs that alter
inspiratory behaviors associated with emesis would be
effective antiemetics. Overall, the newer antiemetic
agents act on pathways related to vagal gastric function
either at the peripheral ending of abdominal vagal affer-
ents or in the area postrema and DVC. Thus, 5-HT
3
–
receptor antagonists are an effective and rational ap-
proach for preventing vagal afferent signaling to the
hindbrain. It is unclear whether alteration of fundic re-
laxation is a component of the antiemetic effects of such
agents as dronabinol or NK
1
R antagonists, although cer-
tainly these agents act in the DVC to mediate their effects.
Possibly, drugs that alter motility may be effective anti-
nausea/antiemetic agents. An enigmatic facet of this ap-
proach is the fact that both tachygastria and bradygastria
are associated with nausea. Therefore, it is not easy to
predict the effects of drugs that alter motility on nausea
and vomiting. For example, a motilin receptor agonist,
ABT-229, with prokinetic effects by means of stimulation
of enteric nerves or on smooth muscle
53
worsens the
A Symposium: Central Nervous System Emetic Circuitry/Hornby
110S December 3, 2001 THE AMERICAN JOURNAL OF MEDICINE威Volume 111 (8A)
symptoms of nausea and vomiting in patients with func-
tional dyspepsia and seems to be of limited usefulness.
54
Finally, although antiemetic drugs are available that are
effective for acute chemotherapeutic-induced emesis,
there are few effective treatments for delayed emesis or
CVS.
ACKNOWLEDGMENT
I appreciate the editorial assistance of Melissa Burmeister.
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