Neurotransmitters in hiccups

Abstract

Hiccups are the sudden involuntary contractions of the diaphragm and intercostal muscles. They are generally benign and self-limited, however, in some cases they are chronic and debilitating. There are approximately 4000 admissions for hiccups each year in the United States. The hiccup reflex arc is composed of three components: (1) an afferent limb including the phrenic, vagus, and sympathetic nerves, (2) the central processing unit in the midbrain, and (3) the efferent limb carrying motor fibers to the diaphragm and intercostal muscles. Hiccups may be idiopathic, organic, psychogenic, or medication-induced. Data obtained largely from case studies of hiccups either induced by or treated with medications have led to hypotheses on the neurotransmitters involved. The central neurotransmitters implicated in hiccups include GABA, dopamine, and serotonin, while the peripheral neurotransmitters are epinephrine, norepinephrine, acetylcholine, and histamine. Further studies are needed to characterize the nature of neurotransmitters at each anatomical level of the reflex arc to better target hiccups pharmacologically.

Full text

Nausheen et al. SpringerPlus (2016) 5:1357
DOI 10.1186/s40064-016-3034-3
REVIEW
Neurotransmitters inhiccups
Fauzia Nausheen1, Hina Mohsin2 and Shaheen E. Lakhan1,2*
Abstract
Hiccups are the sudden involuntary contractions of the diaphragm and intercostal muscles. They are generally benign
and self-limited, however, in some cases they are chronic and debilitating. There are approximately 4000 admissions
for hiccups each year in the United States. The hiccup reflex arc is composed of three components: (1) an afferent
limb including the phrenic, vagus, and sympathetic nerves, (2) the central processing unit in the midbrain, and (3)
the efferent limb carrying motor fibers to the diaphragm and intercostal muscles. Hiccups may be idiopathic, organic,
psychogenic, or medication-induced. Data obtained largely from case studies of hiccups either induced by or treated
with medications have led to hypotheses on the neurotransmitters involved. The central neurotransmitters implicated
in hiccups include GABA, dopamine, and serotonin, while the peripheral neurotransmitters are epinephrine, norepi-
nephrine, acetylcholine, and histamine. Further studies are needed to characterize the nature of neurotransmitters at
each anatomical level of the reflex arc to better target hiccups pharmacologically.
Keywords: Hiccup, Neurotransmitters, Therapies
© 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.
Background
e term “singultus” (hiccup) comes from singult; a Latin
word that means ‘sob’ or ‘gasp’. It refers to the sounds
that are produced by the sudden involuntary contrac-
tions of the diaphragm and intercostal muscles followed
by an abrupt contraction of the glottis. e air strikes the
closed glottis and results in the characteristic “hiccup”
sound. Hiccups are usually benign and self-limiting. ey
generally start without any specific reason and disappear
in a few minutes. Brief episodes of hiccups are common
in healthy individuals after a large meal, intake of alco-
holic beverages, or sudden excitement.
is article provides a review of different neurotrans-
mitters that are related in the mechanism of action of
the most commonly used drugs to treat hiccups, and the
medications that induced hiccups. At the end, this paper
draws a conclusion about the neurotransmitters involved
in the pathophysiology of hiccups.
Epidemiology
e classification of hiccups is based on their duration.
An acute attack lasts less than forty-eight hours. Persis-
tent hiccups last more than 2days. Intractable hiccups
are present if the attack lasts more than 1month. Per-
sistent hiccups are most likely to be associated with an
underlying pathological, anatomic or organic disease
process (Cymet 2002). Intractable hiccups that continue
for more than 1month are usually indicative of a seri-
ous organic disturbance (Vaidya 2000). If left untreated,
intractable hiccups can cause severe discomfort, depres-
sion, reduced physical strength, and even death (Con-
sults 2011). According to a report by William H. Dobelle,
approximately 4000 hospital admissions due to hiccups
are reported each year in the United States (Dobelle
1999). e intractable hiccups are more common in men
(82%) than in women. Most of the men suffering from
hiccups are 50years of age or older (Cymet 2002). Psy-
chogenic hiccups have been reported to occur more
commonly in women. e usual rate for hiccups is four
to sixty per minute with fairly constant frequency in an
individual (Howes 2012). Pathological hiccups can be
explained as a form of epilepsy or a failure of supra-spinal
inhibition (Launois et al. 1993; Lewis 1985). e inci-
dence and prevalence of persistent and intractable hic-
cups in the community has not been studied.
Open Access
*Correspondence: slakhan@gnif.org
1 Department of Medical Education, California University of Science
and Medicine - School of Medicine, 1405 W. Valley Blvd, Suite 101, Colton,
CA 92343, USA
Full list of author information is available at the end of the article

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Nausheen et al. SpringerPlus (2016) 5:1357
Pathophysiology
e pathophysiological mechanism of hiccups is related
to lesions in its reflex arc as shown in Fig.1. e reflex arc
is comprised of three components:
1. e afferent limb including phrenic, vagus, and sym-
pathetic nerves to pass on somatic and visceral sen-
sory signals;
2. e central processing unit in the midbrain; and
3. e efferent limb travelling in motor fibers of phrenic
nerve to diaphragm and accessory nerves to the
intercostal muscles, respectively.
e central component is located in the periaque-
ductal grey, subthalamic nuclei (Hansen and Rosenberg
1993) among the brain stem respiratory center, phrenic
nerve nuclei, reticular formation and hypothalamus.
e central component for hiccups lies in the medulla
and is thought to be entirely separate from the pathways
involved in rhythmic breathing (Davis 1970). Dopamine,
gamma-amino-butyric-acid (GABA), serotonin, gluta-
mate, and glycine neurotransmitters can regulate this
central mechanism. e hiccup arc has modulatory input
from catecholaminergic and serotonergic afferents.
e release of 5-hydroxyl-tryptamine (5HT) from the
gut enterochromaffin cells and enteric vagal afferents
may also lead to hiccups as seen in a case report following
administration of cisplatinum, a chemotherapeutic agent
(Jatoi 2009). e mental branch of the trigeminal nerve
was also postulated to develop hiccups when stimulated
via chin shaving (Todisco etal. 2004). Significant nega-
tive intrathoracic pressure may occur during hiccups that
may result in hypotension, bradycardia, pneumomedi-
astinum, and subcutaneous emphysema (Rousseau 1995).
e mechanism of action of hiccups might be mediated
through agonizing 5-HT1A and antagonizing 5-HT2A
receptors to enhance the activity of the phrenic nerve,
thereby inducing hiccups. is concept was supported in
Fig. 1 Hiccup reflex arc with neurotransmitters

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Nausheen et al. SpringerPlus (2016) 5:1357
a case report in which quetiapine was successfully used
to resolve the aripirazole-induced hiccups. is may sug-
gest the partial agonist and relatively high 5-HT1A recep-
tors binding affinities in the pathophysiology of hiccups
(Gilson and Busalacchi 1998). It is postulated in a study
that the GABA-containing cells in the nucleus raphe
are the source of GABA-nergic inhibition of the hiccup
center (Musumeci etal. 2000).
e most commonly used pharmacological treatments
include metoclopramide which reduces the intensity of
esophageal contraction, chlorpromazine (Twycross etal.
2002), baclofen, nifedipine which reverses the abnor-
mal depolarization in the hiccups reflex, valproic acid
that enhances GABA transmission centrally (Smith and
Busracamwongs 2003), antipsychotics, glucagon, GABA
analogue which acts by activating an inhibitory neuro-
transmitter, and dimethlamine derivative of phenothia-
zine which acts centrally by dopamine blockade in the
hypothalamus (Friedman 1996). Baclofen (GABA-ago-
nist) is among the substances that act through the nerv-
ous system and has by far the best ability to treat chronic
hiccups (Guelaud etal. 1995; Oshima etal. 1998; Petroi-
anu etal. 1997; Steger etal. 2015). However, a Cochrane
systemic review found insufficient evidence as to which
pharmacological agent is best for hiccups (Moretto etal.
2013). Hiccups are the manifestation of diaphragmatic
myoclonus and are considered to be a form of physiologic
myoclonus.
Etiology
In the review of recent literature, a variety of hiccups
etiologies have been reported (idiopathic, organic, psy-
chogenic, and medication-induced) induced have been
reported. Table1 provides an overview of pathology that
has been reliably linked to this condition. It has been sug-
gested that damage to the cervical cord, brainstem, hypo-
thalamus, and supra-tentorial area precipitate hiccups by
stimulating the hiccups reflex arc or decreasing the nor-
mal inhibition of hiccup neurons. It is suggested that all
potentially successful therapeutic drugs used to treat hic-
cups either decrease the input from gastrointestinal tract
(GIT) to the hiccups center or decrease the excitability
and output from the hiccups center (Burke etal. 1988;
Petroianu etal. 1997).
Neurotransmitters targets inhiccups
e exact etiology of hiccups is unclear, and it is
unknown why diverse drugs like dopamine blocking
agents (DBA), baclofen, clonazepam, and phenytoin,
which have widely varying mechanisms of action, can
be effective in the treatment of hiccups (Peleg and Peleg
2000). Table2 summarize drugs which induce and treat
hiccups and their potential neurotransmitters.
Gama‑amino butyric acid (GABA)
ere is strong evidence that the GABA is one of the
neurotransmitters involved in the hiccups reflex at the
central level. GABA functions as an inhibitory media-
tor at the interneuron level in the brain and in the spinal
cord (presynaptic inhibition) by altering trans-membrane
potential. Glutamic acid is decarboxylated to produce
GABA by the enzyme -glutamate decarboxylase (Rod-
well 2012). e inhibition of synapses by GABA has been
shown in the cerebellar cortex, hippocampus, olfactory
bulb, cuneate nucleus, caudate nucleus, substantia nigra,
septal nucleus, and between the vestibular and trochlear
Table 1 Common causes ofhiccups
Central nervous system Vascular Stroke, Infarct, SLE related vascular disorders and aneurysm
Infectious Meningitis and Encephalitis
Structural Brain injury, Intracranial tumors
Inflammation Neuromyelitis optica and multiple sclerosis
Miscellaneous Seizure, Parkinson’s Syndrome
Peripheral Nervous System (phrenic, vagal
and sympathetic nerves) Gastrointestinal Hiatus hernia, Esophageal cancer, Gastro-esophageal reflex
disease, stomach volvulus and H.pylori infection, Pancreatitis,
Abdominal abscess and Abdominal tumors
Thoracic Cardiovascular Myocardial Ischemia, Pericarditis, Thoracic Aneurysm
Pulmonary Bronchitis, Pneumonia, Asthma, Bronchial carcinoma, Tuberculosis
Ear, Nose and Throat Rhinitis, Otitis, Pharyngitis, Foreign body in nose or ear
Other causes Toxic metabolic Electrolyte imbalance, Alcohol, Chronic renal failure, Diabetes
mellitus
Pharmacological Steriods, benzodiazepines, chlordiazepoxide, diazepam, antibiot-
ics, sulfonamides, opioids, cisplatinum (Jatoi 2009), analeptic
agent, Methyldopa, l-dopa, Dopamine
Psychosomatic Anxiety, sleep deprivation, stress and fear

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Table 2 List ofdrugs which induce andtreat hiccups andtheir potential neurotransmitters
Location Neurotransmitters Drug‑induced hiccups Treatment ofhiccups
Central neurotransmitters; Respiratory center, medul-
lary reticular formation, phreni**c nerve nuclei,
hypothalamus, temporal lobes
Gama-amino butyric acid (GABA) Propofol (Jones et al. 1995) Valproic acid (Smith and Busracamwongs 2003)
Benzodiazepine (Jones et al. 1995) Baclofen (Guelaud et al. 1995; Oshima et al. 1998;
Petroianu et al. 1997; Smith and Busracamwongs
2003; Zhang et al. 2014)
Barbiturates (MacDonald et al. 1989) Gabapentin (Petroianu et al. 1998, 2000; Moretti et al.
2004; Liang et al. 2005; Porzio et al. 2010)
Midazolam (Smith and Busracamwongs 2003)
Dopamine Aripiprazole (Ray et al. 2009) Metaclopramide (Smith and Busracamwongs 2003;
Stav et al. 1992; Bateman 1983)
Chlorpromazine (Smith and Busracamwongs 2003)
Dopamine agonists (pirebedil, pergolide, pramipexo)
(Sharma et al. 2006; Lester et al. 2007)Baclofen (Martinez-Ruiz et al. 2004)
Clonazepam (Martinez-Ruiz et al. 2004)
Levodopa (Luquin et al. 1992) Phenytoin (Martinez-Ruiz et al. 2004)
Pramipexol (Vaidya 2000; Martinez-Ruiz et al. 2004)
Serotonin Olanzapine (Alderfer and Arciniegas 2006)
Amantadine (Wilcox et al. 2009; Askenasy et al. 1988)
Sertraline (Vaidya 2000)
Tandospirone (Takahashi et al. 2004)
Risperidone (Nishikawa et al. 2015)
Peripheral neuro transmitters; diaphragm, glottis,
scalene muscle, respiratory muscle, GIT Histamine Omeprazole (Petroianu et al. 1997)
Epinephrine Norepine-phrine Methylphenidate (Marechal et al. 2003; Pollock et al.
2009)
Acetylcholine Metoclopramide (Butterworth IV et al. 2005; Smith
and Busracamwongs 2003)

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Nausheen et al. SpringerPlus (2016) 5:1357
motor neurons. ere are three main types of GABA
receptors—GABA-A, -B, and -C. GABA-A are the most
abundant receptors and the site of action of many neuro
active drugs such as benzodiazepines, barbiturates, etha-
nol and volatile anesthetics (Molinoff 2011). Valproic
acid enhances GABA transmission centrally (Smith and
Busracamwongs 2003) and is one of the most commonly
suggested therapies for hiccups. It is postulated in a study
that the GABA-containing cells in the nucleus raphe are
the source of GABA-ergic inhibition of the hiccup center
(Musumeci etal. 2000).
Dopamine
ere are many studies to support the convincing role
of dopamine as the central neurotransmitter involved
in hiccup pathogenesis. Dopamine is found in the brain
and peripherally in the adrenal medulla, plexuses of the
GI tract, and the enteric nervous system. Dopamine is
an adrenergic agonist that is non-selective (Morgan etal.
2005). ere are five dopamine receptor subtypes that
have been delineated by pharmacological analysis that
are the bases of a subtype of selective drugs. ere are
three major dopaminergic pathways in the central nerv-
ous system:
1. the niagrostriatal pathway which is important in Par-
kinson’s disease;
2. the mesolimbic pathway which plays a role in psychi-
atric disorders; and
3. the tuberoinfundibular pathway, which is related to
the regulation of the endocrine system.
Dopamine is an immediate precursor of norepineph-
rine. e synthesis of dopamine can be increased by
giving DOPA (Smith and Busracamwongs 2003; Ash-
ley and Krych 1995). ere are many studies, in which
patients have been treated successfully by using dopa-
mine blocking drugs such as metochlopromide and
chlorpromazine (Smith and Busracamwongs 2003) which
supports the evidence that dopamine acts as the central
neurotransmitter.
5‑Hydroxyl tryptamine (5HT; serotonin)
Many studies support the role of 5HT (serotonin) as the
neurotransmitter of hiccups. Serotonin is an important
central nervous system neurotransmitter and a local hor-
mone. It is also found in high concentrations in entero-
chromaffin cells throughout the GIT that are the site of
synthesis and storage of 5 HT from tryptophan. It regu-
lates the smooth muscles in the GIT to increase the tone
and facilitate the peristalsis via 5HT2 receptors (Katzung
2012). It is a powerful vasoconstrictor mainly through
5HT2 receptor but it dilates the blood vessels of the
heart and skeletal muscles (Katzung 2012). It is produced
in two steps: in step 1, tryptophan in converted to 5HT
and in the next step, the 5HT is converted to serotonin.
Increasing the concentration of tryptophan in the brain
can increase the high concentration of 5HT and sero-
tonin. Drugs that increase serotonin levels were most
commonly used as appetite suppressants. ey regulate
the smooth muscles in the GIT and cardiovascular sys-
tem. ere are fourteen subtypes of receptor of 5HT
recognized. ere are the 5HT1 subfamily and 5HT2
subfamilies of receptors. 5HT3 subfamilies were origi-
nally described in the periphery. ere are fourteen sub-
types of receptor of 5HT recognized. Cases of intractable
hiccups have been successfully treated with olanzapine
(Alderfer and Arciniegas 2006). Olanzapine has a com-
plex pharmacology and its major effect is to antago-
nize the postsynaptic serotonergic receptors. Similarly,
another case was reported describing the successful
treatment of hiccups with sertraline, a selective seroto-
nin reuptake inhibitor (SSRI), for the first time (Benowitz
2012; Vaidya 2000). In one case study, intractable hic-
cups were treated successfully with a tandospirone, a new
anxiolytic and 5HTA1 receptor agonist (Takahashi etal.
2004). Interestingly, a case report of intractable hiccups
that was refractory to the typical antipsychotic haloperi-
dol, however, responsive to atypical antipsychotic risp-
eridone which acts on 5HT2A, 5HT1A, 5HT1C, 5HT1D,
and D2 receptors (Nishikawa etal. 2015). All these stud-
ies are evidence that serotonin is involved in the patho-
physiology of hiccups.
Histamine
Histamine is produced by decarboxylation of histadine,
an amino acid, by the enzyme histadine decarboxylases
(Biomedical Aspects of Histamine 2011).
Histamine is released by the various triggers from mast
cells and basophils and has various biological effects
through four receptors H1R, H2R, H3R, H4R. Hista-
mine causes smooth cell contractions, vasodilatation,
and gastric acid secretion. Hyperhistaminemia can cause
an anaphylactic reaction (Hershko etal. 2001). ere is
evidence for the use of H2-receptor blockers and proton
pump inhibitors (i.e. omeprazole) for the treatment of
hiccups thought to act via decreasing the input from the
GIT to the hiccup center (Petroianu etal. 1997).
Epinephrine andnorepinephrine (NE)
Noreepinephrine (NE) is the neurotransmitter of the
post ganglionic autonomic nervous system that is
involved in the reduction of gastrointestinal motility.
NE is synthesized from tyrosine that is produced from
phenyle alanine. Dopamine is converted to NE by dopa-
mine beta hyroxylases. Norepinephrine is converted

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Nausheen et al. SpringerPlus (2016) 5:1357
to epinephrine by the enzyme phenyle ethanolamine-
N-methyltransferase. e action of neurotransmit-
ter catecholamines is terminated by the re-uptake
and metabolism by the enzymes monoamine oxidases
(MOA) and catecolaminotransferases (COMT). e
inhibitors of these enzymes are used in the treatment
of Parkinson’s disease. Adreno receptors have four sub-
types, alpha1, alpha2, and beta1 for NE mainly and B2
is for epinephrine mainly. ere are studies about the
successful treatment of hiccups with methylphenidate
(a psycho-stimulant) generally used in attention deficit
disorders (Marechal etal. 2003; Pollock etal. 2009). e
methylphenidate is considered as the receptor modula-
tor of dopamine and norepinephrine. erefore relation-
ship may exist between norepinephrine and epinephrine
to the pathophysiology of hiccups.
Acetylcholine
Acetylcholine is a naturally occurring neurotransmit-
ter for the muscarinic receptors. It is a neurotransmitter
of all the preganglionic autonomic fibres, most post-
ganglionic parasympathetic, and a few post-ganglionic
sympathetic fibers (Westfall and Westfall 2011). Meto-
clopramide, an anticholinergic, is recommended for the
symptomatic relief of hiccups. ere are studies that
show that metoclopramide acts peripherally to reduce
the intensity of esophageal contraction (Consults 2011).
It has also been observed that metoclopramide have been
used to treat hiccups (Smith and Busracamwongs 2003)
which may explain the relation of acetylcholine as the
peripheral neurotransmitter involved in the pathophysi-
ology of hiccups.
Conclusion
Largely through case studies involving medications, we
implicate the neurotransmitters involved in hiccups. e
reflex arc is potentially mediated by central neurotrans-
mitters (GABA, dopamine, and serotonin) and peripheral
neurotransmitters (epinephrine, norepinephrine, acetyl-
choline, and histamine). Lesions across any of these neu-
roanatomical structures, for instance, from the brainstem
down to the diaphragm, may be responsible for the devel-
opment of hiccups. Further research is needed to char-
acterize the neurotransmitters involved in hiccups for
potential new therapeutic targets.
Authors’ contributions
Conceived and designed the paper: FN, HM, SEL. All authors participated in
the preparation of the manuscript. All authors read and approved the final
manuscript.
Author details
1 Department of Medical Education, California University of Science and Medi-
cine - School of Medicine, 1405 W. Valley Blvd, Suite 101, Colton, CA 92343,
USA. 2 Department of Neurology, California University of Science and Medicine
- School of Medicine, Colton, CA, USA.
Acknowledgements
We would like to extend our thanks to the Chair, Professor and Associate
Dean for Clinical Research, Department of Cellular Biology and Pharmacol-
ogy Florida International University, Dr. Georg Petroianu. Without his help
and guidance this review would have not been possible. It is our pleasure to
convey our gratitude to him in our humble acknowledgement. Also, we wish
to thank Ellen Wilkinson and Nancy Bethel of California University of Science
and Medicine for their editing support, guidance, and suggestions.
Competing interests
The authors declare that they have no competing interests.
Received: 9 March 2016 Accepted: 10 August 2016
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