Re iew A icle
Idiopa hic Neck Pain o Neck Pain o Gas ic O igin? A Sys ema ic
Re iew o Ra Expe imen al S udies on Gas ic Ha m
Pa hophysiology and The apy
´
Angel Oli a-Pascual-Vaca ,
1
,
2
,
3
Ignacio Na a o-Ca mona ,
2
,
3
Jes´
us Oli a-Pascual-Vaca ,
1
,
2
,
3
Inmaculada Riquelme ,
4
,
5
,
6
Luis Gab iel Luque-Rome o ,
7
,
8
and Jos´
eManuel L´
opez-Mill´
an
9
,10
1
Ins i u o de Biomedicina de Se illa-IBiS, Hospi ales Uni e si a ios Vi gen del Roc´ıo y Maca ena, CSIC, Uni e sidad de Se illa,
Se ille, Spain
2
Depa amen o de Fisio e apia, Facul ad de En e me ´
ıa, Fisio e apia y Podolog´
ıa, Uni e sidad de Se illa, Se ille, Spain
3
Escuela de Os eopa ´ıa de Mad id, Mad id, Spain
4
Resea ch Ins i u e on Heal h Sciences (IUNICS), Uni e si y o Balea ic Islands, Palma de Mallo ca, Spain
5
Depa men o Nu sing and Physio he apy, Uni e si y o Balea ic Islands, Palma de Mallo ca, Spain
6
Heal h Resea ch Ins i u e o he Balea ic Islands (IdISBa), Palma 07010, Spain
7
Unidad de In es igaci´
on, Dis i o Alja a e y Se illa No e, Se icio Andaluz de Salud, Se ille, Spain
8
Depa amen o de Medicina P e en i a y Salud P´
ublica, Facul ad de Medicina, Uni e sidad de Se illa, Se ille, Spain
9
Depa amen o de Anes esiolog´
ıa y Medicina Del Dolo , Hospi al Uni e si a io Vi gen Maca ena, Se ille, Spain
10
Depa amen o de Ci ug´ıa, Uni e sidad de Se illa, Se ille, Spain
Co espondence should be add essed o Ignacio Na a o-Ca mona; [email p o ec ed]
Recei ed 3 Decembe 2024; Accep ed 18 Ap il 2025
Academic Edi o : Woon-Man Kung
Copy igh ©2025 ´
Angel Oli a-Pascual-Vaca e al. In e na ional Jou nal o Clinical P ac ice published by John Wiley & Sons L d.
Tis is an open access a icle unde he e ms o he C ea i e Commons A ibu ion License, which pe mi s use, dis ibu ion and
ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
Backg ound: Mos cases o neck pain a e classi ed as nonspeci c o idiopa hic pain and show cha ac e is ics such as sensi iza ion,
hype algesia, limi ed ange o mo ion, and muscle spasm. Visce al diso de s can igge all hose ea u es, and gas ic diso de s a e
ela ed o neck pain. Fu he mo e, s ess and anxie y a e equen ly soma icized as neck pain. Howe e , i s pa hophysiological link
has ne e been de e mined.
Objec i es: To iden i y he elec omyog aphic and pos u al esponse o expe imen al gas ic insul in a s.
Me hods: A sys ema ic e iew was unde aken. Sea ches we e conduc ed in he PubMed and Web o Science da abases. Te da e
o publica ion was no limi ed. Re e ences om included a icles we e assessed. Te sample, expe imen al in e en ion, and he
esul s we e e ie ed om each s udy.
Resul s: Six een s udies we e included. Ac omio apezius muscle showed he highes ac i i y o gas ic damage, being up o
8–10 imes highe han abdominal muscles con ac ion. Also, a pos u al esponse compa ible wi h neck muscles spasm was
obse ed. Te h eshold o eaching ce ical spasm was lowe ed by he addi ion o s ess, gas i is, dyspepsia, ulce s, diabe es, o
in amma ion o he colon. Inc eased isce omo o esponse pe sis ed e en mo e han 60 days a e gas ic insul , despi e no
ob ious inju y was al eady isible in he s omach. Fu he mo e, p ena al o neona al gas ic inju y also p oduced gas ic hy-
pe sensi i i y and inc eased apezius spasm in adul a s. On he con a y, neck spasm was educed by e e sing diabe es o
blocking he gas ic ecep o s and i s a e en pa hways.
Conclusions: Gas ic ha m igge s neck muscles spasm. Since many gas ic condi ions and hype sensi i i y a e common and
end o be ch onic, his may con ibu e o explain he pe sis ence o neck pain and sensi iza ion in many pa ien s. P ena al and
neona al gas oin es inal su e ing inc eases apezius isce omo o esponse in adul s. Fu he mo e, ou ndings migh con-
ibu e o explain why s ess is equen ly soma icized as neck pain.
Keywo ds: anxie y; diabe es; elec omyog aphy; unc ional dyspepsia; neck pain; pep ic ulce ; psychological s ess; s omach
Wiley
In e na ional Jou nal o Clinical P ac ice
Volume 2025, A icle ID 8835586, 14 pages
h ps://doi.o g/10.1155/ijcp/8835586
1. In oduc ion
Neck pain has a high impac in socie y, wi h a p e alence o
27.0 pe 1000 inhabi an s in 2019 [1]. I is mo e common in
women [2], and i cons i u es he ou h cause o disabili y,
wi h a cos o 134 million USD i added o low back pain [1].
When a pa hoana omical cause has been diagnosed,
pa ien s a e ca ego ized as su e ing speci c neck pain, such
as a ch onic heuma ic disease [3], ace join pain [4], disc
he nia ion [5] o adiculopa hy [6]. Howe e , mos cases a e
classi ed as nonspeci c because he e iology has no been
de e mined [7].
Mo e han 40% o wo ldwide popula ion su e s om
unc ional gas oin es inal diso de s [8]. Rega ding unc-
ional dyspepsia, i esul s om a combina ion o isce al
hype sensi i i y, gas ic mo o dys unc ion, and psycho-
logical issues [9], and i s p e alence anges be ween 7% and
34.2% a ound he wo ld. Mos epidemiological s udies did
no nd be ween-sex di e ences in p e alence da a, bu
some o he s epo ed a highe a io in emale popula ion
[10]. Mo eo e , me abolic diso de s cause isce al hype -
sensi i i y [11, 12], which acili a es he de elopmen o
gas oin es inal diso de s. Tus, 75% o diabe es melli us
pa ien s show diges i e issues [13]. Rega ding o he gas ic
diso de s, he p e alence o pep ic ulce in he wo ld is 8.4%
[14], while in 2019, he e we e 783.95 million cases o
gas oesophageal e ux globally, wi h inc easing p e alence
o 77.53% be ween 1990 and 2019 [15].
Skele al muscles a e esponsible o p o iding suppo and
s abili y o he body, as well as enabling mo emen . In addi ion,
hey a e also in ol ed in p o ec ing he body agains inju y. In
esponse o issue su e ing, skele al muscles exhibi e ex
con ac ion ac i i y as a p o ec i e mechanism ha helps o
p e en u he damage o he a ec ed s uc u e by means o
he adop ion o a ce ain pos u e and limi ing he mo emen o
ha a ea [16]. Fo ins ance, hose muscles whose con ac ion
p o ec s he ne es a e p og essi ely ec ui ed in a e ex
manne as he s ess inc eases in he neu al issues [17]. Tis
way, pa ien s wi h disc he nia ion and scia ica end o p esen
muscula con ac u e which usually is accompanied by
a cha ac e is ic an algic pos u e [18]. Tis kind o ac i i y has
been obse ed no only in he case o soma ic issues bu also
o isce al ones. Tus, i is gene ally well known ha kidney
diso de s end o p oduce hype onus in lumboabdominal
muscles [16]. Ano he example could be he abdominal spasm
in pe i oni is. Howe e , he musculoskele al spasm which is
gene a ed because o gas ic su e ing is no so well ecognized
[19]. Tus, i seems in e es ing o de e mine which is he
musculoskele al con ac u e because o s omach diso de s.
Te aim o his s udy is o sys ema ically e iew s udies
ha analyze he elec omyog aphic and pos u al esponse o
expe imen al gas ic insul and/o dis ess in a s.
2. Ma e ial and Me hods
Tis sys ema ic e iew has been pe o med acco ding o he
P e e ed Repo ing I em o Sys ema ic Re iews and Me a-
Analyses (PRISMA) guidelines [20]. I was egis e ed in he
In e na ional P ospec i e Regis e o Sys ema ic Re iews
(PROSPERO), wi h egis a ion numbe CRD42022362341.
2.1. Sea ch S a egy. Two au ho s conduc ed he sea ch
be ween No embe 9
h
2022 and Janua y 9
h
2023 using he
PubMed and Web o Science da abases. Te sea ch s a egy
used was (elec omyog aph
∗
OR pos u
∗
) AND (gas ic
∗
OR
gas o
∗
OR diges i
∗
OR s omach
∗
) AND ( a OR a s OR
mouse OR mice) NOT gas ocnemi
∗
. Te da e o publica ion
was no limi ed. Re e ence lis s we e checked o include any
o he a icle ha me he cha ac e is ics sough . In case o
disag eemen s, a hi d esea che sol ed he issue.
2.2. Selec ion C i e ia. We included s udies abou he elec-
omyog aphic and/o pos u al consequences o expe i-
men al gas ic dis ess in a s and mice, published ei he in
Spanish o English. Te selec ion o a icles was ca ied ou
by wo esea che s acco ding o he inclusion and exclusion
c i e ia. Disag eemen s we e sol ed by ano he esea che .
2.3. Da a Ex ac ion and Me hodological Quali y Assessmen .
Te bibliog aphical e e ence, sample, expe imen al in-
e en ion, and esul s we e e ie ed om each s udy.
Fu he mo e, a modi ed e sion o he Sys ema ic Re iew
Cen e o Resea ch o Labo a o y Animal Expe imen a ion
(SYRCLE) [21] isk o bias ool was used o assess he
me hodological quali y o he selec ed a icles. Tis in-
s umen assesses he isk o bias o animal in e en ion
s udies, hus sco ing he in e nal and ex e nal alidi y. All
his in o ma ion was collec ed by wo esea che s ollowing
s anda dized o ms, and disag eemen s we e esol ed by
ano he esea che .
3. Resul s
F om he li e a u e sea ch, 1181 s udies we e iden i ed.
A e eading i les and abs ac s, and a e conside ing he
‘ci ed-by’ e e ences, 227 ull- ex a icles we e assessed o
eligibili y, wi h nally 16 s udies included in he sys ema ic
e iew. Figu e 1 shows he ow diag am.
3.1.Sample. A o al o 789 a s we e included in he e iewed
s udies, wi h 44 being emale Sp ague–Dawley [22], 32 male
Wis a [23], and 713 male Sp ague–Dawley.
3.2. Gas ic Ha m. As an inju y o he s omach, all he
s udies pe o med gas ic dis ension wi h an in agas ic
balloon. In some s udies, ha was he unique ha m applied
o he animals [23, 24]. In o he in es iga ions, chemical o
me abolic insul was u he induced [22, 25–36]. Tus, he
s udies used HCl [28] o ace ic acid [27–29, 33, 34] o
p oduce gas ic ulce s o iodoace amide o cause gas i is
[25, 26, 28, 29, 31–33, 35, 36]. In addi ion o cause unc ional
dyspepsia o he a s by using iodoce amide, u he gas ic
2In e na ional Jou nal o Clinical P ac ice
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ha m was ob ained s essing he a s, ei he placing hem in
a small cylind ic ube [36] o clamping hei ails [26].
Ano he s udy achie ed gas ic hype sensi i i y by injec ing
co icos e oids [30], while o he did so by inducing diabe es
h ough s ep ozo ocine injec ion [22]. One s udy assessed
gas ic hype sensi i i y a e chemical in amma o y insul
o he dis al colon by means o ini obenzene sul onic acid
[37]. Finally, ano he s udy induced p ena al ma e nal s ess
and es ed he gas ic hype sensi i i y o he o sp ing by
gas ic dis ension in adul hood [38].
3.3. P ena al and Neona al Gas ic Inju y. Six s udies pe -
o med gas ic inju y ( unc ional dyspepsia model) when he
a s we e newbo n, om one o en days old
[25, 26, 31, 32, 35, 36] and assessed he consequences when
he a s we e adul s (6–12 weeks old), showing also enhanced
isce omo o esponse. One o hose in es iga ions did no
di ec gas ic inju y bu did colon in amma ion du ing s
days o li e, esul ing simila ly in adul gas ic hype sensi-
i i y and neck spasm [35].
3.4. Pos u al Response. Te obse ed eac ions om
15 mmHg o gas ic dis ension we e aising and u ning
on bo h sides o he head, co esponding o con ac ions
o he neck muscles [23]. Tis eac ion was also desc ibed
as b ie head mo emen ollowed by immobili y [31]. As
gas ic inju y inc eases, abdominal muscles con ac ed,
ollowed by abdominopel ic li ing and s e ching o
body [25, 31]. Fu he gas ic ha m by 6 days o o al
ga ages wi h iodoace amide enhanced he pos u al e-
sponses o gas ic dis ension a 8 weeks compa ed wi h
con ols [31].
Reco ds iden i ied om:
Da abases (n = 1667)
PubMed (n = 450)
Web o Science (n = 1217)
Reco ds emo ed be o e sc eening:
Duplica e eco ds emo ed (n = 383)
O he languages (n = 103)
Reco ds ma ked as ineligible by au oma ion
ools (n = 0)
Reco ds emo ed o o he easons (n = 0)
Reco ds sc eened
(n = 1181)
Reco ds sough o e ie al
(n = 224) Reco ds no e ie ed
(n = 0)
Full- ex a icles assessed o
eligibili y
(n = 227)
S udies included in he e iew
(n = 16)
Iden i ica ion
Sc eening
Included
Reco ds excluded (n = 957):
No s udy elec omyog aphy o pos u e
(n = 387)
O he isce a (n = 423)
No expe imen al s udies (n = 99)
S udy o mo e han one isce a (n = 48)
Repo s om e e ences lis s
(n = 3)
Reco ds excluded (n = 211):
No s udy elec omyog aphy o pos u e
(n = 37)
O he isce a (n = 74)
S udy o mo e han one isce a (n = 56)
No epo elec omyog aphic da a (n = 12)
Figu e 1: PRISMA owcha o he s udy selec ion p ocess. PRISMA, p e e ed epo ing i ems o sys ema ic e iews and me a-analyses.
∗
Conside , i easible o do so, epo ing he numbe o eco ds iden i ed om each da abase o egis e sea ched ( a he han he o al
numbe ac oss all da abases/ egis e s).
∗∗
I au oma ion ools we e used, indica e how many eco ds we e excluded by a human and how
many we e excluded by au oma ion ools. F om: Page MJ, McKenzie JE, Bossuy PM, Bou on I, Ho mann TC, Mul ow CD, e al. Te
PRISMA 2020 s a emen : An upda ed guideline o epo ing sys ema ic e iews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71. Fo mo e
in o ma ion, isi : h ps://www.p isma-s a emen .o g/.
In e na ional Jou nal o Clinical P ac ice 3
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3.5. Elec omyog aphic Response. Te 16 s udies included in
his e iew assessed he muscula ac i i y in he neck as
a me hod o eco d i gas ic inju y had been achie ed. All
he 16 s udies egis e ed an inc ease in neck muscles con-
ac ion because o expe imen ally de eloped gas ic ha m.
Te mos ancien o he s udies s a es ha hei p elimina y
obse a ions showed ha gas ic dis ension in a s did no
induce abdominal con ac ions, as did colo ec al dis ension,
bu aised he head and s e ching o he body [23]. Tus,
hey placed he elec odes in he neck muscles, wi h no
u he in o ma ion abou he speci c loca ion. A e ha ,
Ozaki e al. [33] e alua ed he elec omyog aphic esponse in
he ec us abdominus, ex e nal oblique, ac omio apezius,
spino apezius, and s e nomas oideus. Te highes con-
ac ion esponse was ound in ac omio apezius, ollowed
by spino apezius and s e nomas oideus. Ac omio apezius
showed up o 8–10 imes highe le els o con ac ion
compa ed wi h abdominal muscles and spino apezius and
s e nomas oideus up o doubled abdominal ac i i y. F om
hen on, all o he 14 s udies egis e ed he elec omyo-
g aphic esponse in he ac omio apezius muscle.
Mechanic dis ension o he s omach has p o en o
igge neck spasm by i s own [23, 24]. A lowe gas ic
dis ension is needed o achie e he same neck elec o-
myog aphic esponse in he case o adding s ess [36],
a chemical inju y o cause gas ic ulce s [27–29, 33, 34] o
gas i is [25, 28, 31–33, 35, 36], o me abolic inju y o cause
isce al hype sensi i i y by diabe es [22].
3.6. Te apeu ic In e en ions. Some o he s udies es ed
he apeu ic o inhibi o y p ocedu es, such as mo phine
sul a e [23], splanchnic ne e esec ion, ago omy [34, 38],
chemical dene a ion wi h capsaicin [28], inhibi o s o ion
channels o gas ic a e en p ima y neu ons [24, 35, 38],
ne e g ow h ac o neu aliza ion [25, 29, 35], blocking o
b ain-de i ed neu o ophic ac o in he do sal oo ganglia
[35], gas ic elec ic s imula ion [25, 34], elec oacupunc u e
[32, 36], ad eno ecep o an agonis s (p op anolol and
phen olamine) [32, 35, 36], an agonis s o glucoco icoid
ecep o s [35], he inhibi ion o he consequences o diabe es
by means o aminooxyace ic acid, and inhibi o s o p o ein
kinase A and C, o inhibi he e ec s o co icos e oids [30].
All o hese p ocedu es o he ea men o he s omach o
i s a e en s pa hways implied a educ ion in neck spasm in
all o he s udies, wi h he only excep ion o inhibi o s o
p o ein kinase A [30]. Also, splanchnic ne e esec ion
a oided he neck spasm du ing mechanical insul bu no
du ing chemical insul [28]. On he con a y, ago omy
a oided i du ing chemical agg ession bu no du ing me-
chanical ha m [24].
Fu he mo e, some in e en ions we e pe o med o
block he he apeu ic e ec s. Tus, neck muscles spasm
inc eased by he applica ion o an agonis s o opioid e-
cep o s such as naloxone [23, 25, 34] and CTOP [25].
To nish wi h, he K
1.1 ion channel seems o be also
in ol ed in he inhibi ion o his isce omo o esponse
since he dec ease in he exp ession o his ion channel in
DRG neu ons inc eases EMG esponse o GD [35].
Table 1 summa izes he s udies (Table 1).
3.7. Risk-o -Bias Assessmen . In mos s udies, mul iple isk-
o -bias domains we e assessed as unclea due o poo
epo ing o s udy me hodology. Fou s udies (25%) e-
po ed g oups wi h simila baseline cha ac e is ics, while all
bu one o he emaining s udies was assessed as unclea .
Only one s udy used some o m o andom selec ion du ing
ou come assessmen , and he e was some o m o blinding in
ou s udies (25%). Howe e , he isk o a i ion bias was
high in only wo s udies (12.5%). All s udies we e assessed as
p esen ing low isk o selec i e ou come epo ing and none
o hem we e assessed as high isk o o he biases (Figu e 2).
4. Discussion
4.1. Elec omyog aphic and Pos u al Response. Ou aim was
o analyze he elec omyog aphic and pos u al esponse o
expe imen al gas ic inju y in a s. Acco ding o ou esul s,
he main muscle spasm occu s in he neck, especially in he
ac omio apezius muscle, igge ing pos u al neck conse-
quences such as aising and u ning he head, o neck
immobili y. Inc easing gas ic ha m igge s abdominal
muscles con ac u e, body s e ching, and spine a ching
[31]. I is in e es ing o no e ha his neck spasm happened
in e e y single s udy. In ac , i seems ha i happens in e e y
single a since no au ho decla es ha some a s do no
show ha ac i i y i damage is p esen . So, ou esul s show
ha he neck soma iza ion is he ule in gas ic su e ing.
Ou ndings in expe imen al s udies o gas ic ha m ag ee
wi h hose clinically obse ed in human popula ion su e ing
o icollis caused by gas oesophageal e ux. I is known as
Sandi e synd ome, and i is usually misdiagnosed [39, 40]. I
p esen s neck spasm and e en spine a ching in se e e cases.
Te pa hophysiological basis is hough o be a p o ec i e
isce osoma ic e ex o a oid aspi a ion o he gas ic con en
and con ibu e o emp y he esophagus [39, 41].
Tese soma ic consequences o isce al diso de s a e
gene ally well known o s uc u es such as he kidney [16].
Clinicians and pa ien s use o de ec qui e well when he
lumba spasm, hype sensi i i y, and p o ec i e pos u e is he
consequence o enal su e ing, such as in he case o
neph oli hiasis. Howe e , hey do no ecognize i in he case
o gas ic diso de s and neck pain [19].
As p e iously exposed, 90% o neck pain a e classi ed as
nonspeci c, mechanical, o idiopa hic. Tey a e cha ac e -
ized by pain, sensi iza ion, hype algesia, muscle hype onus,
and limi ed ange o mo ion [42]. All hese ea u es can be
a consequence o a isce al diso de [16, 43].
4.2. A e en Pa hways. Visce al pain is e e ed o soma ic
a eas known as head zones [44]. Te isce al e e ed pain, and
seconda y hype algesia, occu s in a eas neu ome ically con-
nec ed o he o gan [45, 46]. In he case o he s omach, he
head zones a e he neck, he epigas ic, and he in e scapula
a ea [47]. Te ph enic ne es (C3–C5) a e known o supply he
s omach [48–51] and so does he agus ne e. Tus, he a e en
discha ge sensi izes he uppe cen al ne ous sys em, causing
4In e na ional Jou nal o Clinical P ac ice
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Table 1: Syn hesis o he included s udies.
Au ho , yea Sample Gas ic insul Elec omyog aphy Te apeu ic o
inhibi o y p ocedu e O he s
Rouzade e al.,
1998 [23] 32 male Wis a a s GD by in agas ic balloon
EMG o he neck muscles. A o al o
15 o 20 mmHg GD: EMG ac i i y
inc eased be ween 192% and 705%.
When he dis ension p ocedu e was
epea ed 2, 4, and 7 days a e he s
one, he pain h eshold was no
di e en in espec o he s day
4 mg/kg o in ape i oneal mo phine
sul a e signi can ly inc eased pain
h eshold
2.5 mg/kg o naloxone e e sed he
e ec s o mo phine
Ozaki e al.,
2002 [33] 83 male Sp ague–Dawley a s
GD by in agas ic balloon in he
h ee g oups. G oup 1: mul iple
small ulce s we e p oduced by
injec ing 10 μL o 20% ace ic acid
in o 20 si es in he submucosal laye
o he s omach. G oup 2: a single
injec ion o 30 μL o 20% ace ic acid
p oducing a single ulce . Con ols:
Iden ical injec ion o s e ile saline.
G oup 3: d inking wa e wi h IA
0.1% o p oduce gas i is. Con ol
g oup: wa e wi h he same pH
EMG o ac omio apezius,
spino apezius, s e nomas oideus,
ec us abdominus, and ex e nal
oblique muscles. F om 40 mmHg GD,
ac omio apezius EMG ac i i y
inc eased mo e han 400%.
Spino apezius and s e nomas oideus
EMG inc eased mo e han 100%.
Abdominal muscles ba ely
esponded. Ra s wi h mul iple ulce s
inc eased esponse om 10 mmHg
GD up o 60 days a e inju y. Ra s
wi h a single ulce showed modes
inc eased esponse bu did no di e
om con ols. Ra s ea ed wi h IA
inc eased esponse om 40 mmHg
GD 7 days a e beginning he inju y
Inc eased isce omo o esponse
pe sis ed o 60 days a e ace ic acid
ea men in spi e ha ulce s had
healed, p o ed by mac oscopic and
his ological assessmen . Howe e ,
gas ic in amma ion was s ill p esen
acco ding o myelope oxidase ac i i y.
No mal s omachs 60 days a e limi ed
(7 days) IA exposu e did no show
inc eased isce omo o esponse
In e na ional Jou nal o Clinical P ac ice 5
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Table 1: Con inued.
Au ho , yea Sample Gas ic insul Elec omyog aphy Te apeu ic o
inhibi o y p ocedu e O he s
Lamb e al.,
2003 [28] 56 male Sp ague–Dawley a s
GD by in agas ic balloon.
Ins illa ion o 750 μL o 0.05, 0.15, o
0.3 mol/L o HCl. Con ols:
ins illa ion o 750 μL s e ile saline.
G oup 1: injec ion o 100 μL 60%
ace ic acid o p oduce an ulce .
Con ols: injec ion o 100 μL o
s e ile saline. G oup 2: d inking
wa e wi h IA 0.1% o 5 days o
p oduce gas i is. Con ols: wa e
wi h he same pH
EMG o ac omio apezius.
Ins illa ion o saline did no change
EMG ac i i y bu 0.15 and 0.3 mol/L
o HCl inc eased isce omo o
esponse a 2 min and emained
ele a ed o 30 min in spi e ha no
mac oscopic lesions we e seen and
submucosa was his ologically in ac .
Howe e , he e we e occasional ed
blood cells adhe ed o he gas ic
epi helium and dila ed essels. One
hou a e adminis a ion o 0.15 o
0.3 mol/L HCl, he isce omo o
esponse had dec eased o 87% ±11%
o con ol. IA inc eased EMG ac i i y
in spi e ha i did no cause
mac oscopic lesions. Saline did no
igge isce omo o esponses in a s
wi h gas ic ulce s, bu 0.05 mol/L
HCl inc eased EMG ac i i y
Vago omy did no al e he esponse o
mechanical s imula ion bu blun ed
he chemical s imula ion. On he
con a y, splanchnic ne e esec ion
blun ed mechanical s imula ion bu
did no a ec he isce omo o
esponse o acid s imula ion. Chemical
dene a ion by capsaicin also
supp esses he isce omo o esponse
o chemical inju y. In p esence o
ulce s, ago omy signi can ly blun ed
he EMG esponse o HCl compa ed
wi h splanchnic ne e esec ion
Lamb e al.,
2003 [29] 28 male Sp ague–Dawley a s
GD by in agas ic balloon.
Injec ion o 100 μL 60% ace ic acid
o p oduce kissing ulce s. Con ols:
injec ion o 100 μL o s e ile saline
EMG o ac omio apezius. Ulce s
inc ease isce omo o esponse
Neu alizing NGF an ibodies injec ion
diminished gas ic in amma ion and
isce omo o esponse
Kang e al.,
2005 [27] 25 male Sp ague–Dawley a s
GD by in agas ic balloon.
In aluminal injec ion o 100 μL
60% ace ic acid o p oduce kissing
ulce s. Con ols: injec ion o 100 μL
o s e ile saline
EMG o ac omio apezius. GD
igge ed inc eased EMG ac i i y o
a leas 14 days in he expe imen al
g oup e en when he ini ial inju y was
healed. A e 6 weeks, no mac oscopic
lesions we e obse ed and no
di e ences o GD we e ound
be ween g oups
In amma ion di ec ly al e s gas ic
senso y and mo o unc ion. Inc eased
ac i a ion o a e en s igge s
ago agal e exes
Liu e al., 2008
[31]
10 male neona al
Sp ague–Dawley a s (1 day old)
GD by in agas ic balloon. Mild
ansien in amma ion o he
su ace epi helium o he gas ic
mucosa by 0.2 mL 0.1% IA in 2%
suc ose daily by o al ga ages o
6 days. Con ols: 2% suc ose
EMG o ac omio apezius. A e
8 weeks, compa ed wi h con ols, a s
wi h gas ic i i a ion exhibi ed
signi can inc eases in EMG ac i i y
a GD p essu es o 60 (196.1% s.
147.5%) and 80 mmHg (271.2% s.
205.5%). A end owa d an inc ease
was also seen a 40 mmHg (141.9% s.
112.1%)
Gas ic i i a ion in he neona al
pe iod can esul in ch onic gas ic
hype sensi i i y in adul s e en in he
absence o signi can de ec able gas ic
pa hology
6In e na ional Jou nal o Clinical P ac ice
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Table 1: Con inued.
Au ho , yea Sample Gas ic insul Elec omyog aphy Te apeu ic o
inhibi o y p ocedu e O he s
Kondo el al.,
2009 [24] 152 male Sp ague–Dawley a s GD by in agas ic balloon.
Con ols: a s wi hou s imula ion
EMG o ac omio apezius. 60 mmHg
o GD led o an inc ease in
ac omio apezius EMG ac i i y
In a hecal injec ion o TRPA1
an isense educed isce omo o
esponse and supp essed ERK1/2
ac i a ion in he do sal oo ganglion
bu no in he nodose ganglion.
In a hecal and in ape i oneal
injec ions o he TRPA1 inhibi o
HC-03003 supp essed he esponse o
noxious GD
Splanchnic ne e bila e al esec ion
signi can ly educed he isce omo o
esponse o GD whe eas
subdiaph agma ic ago omy did no
di e om sham-ope a ed a s
Zhang e al.,
2013 [22] 44 emale Sp ague–Dawley a s
GD o 60–120 mmHg by in agas ic
balloon. A single in ape i oneal
injec ion o STZ o induce diabe es
melli us, in o de o gene a e gas ic
hype sensi i i y. Con ols: sol en
(ci a e bu e )
EMG o ac omio apezius. Diabe ic
a s showed inc eased EMG ac i i y a
p essu es o 60, 80, 100, and
120 mmHg
CBS inhibi o AOAA (5 and 10 mg/kg)
ea men diminishes
ac omio apezius EMG esponse o
GD
Epigene ic egula ion migh be
in ol ed in he de elopmen o gas ic
hype sensi i i y by enhancing nuclea
ac o -kB-media ed CBS gene
exp ession
Wins on and
Sa na, 2013
[35]
132 male Sp ague–Dawley adul
a s and 10-day-old pups
GD o 30–120 mmHg by in agas ic
balloon. G oup colon in amma ion:
adul s and pups ecei ed 0.2 mL o
130 mg/kg ini obenzene sul onic
acid in 10% e hanol in saline
h ough a ube inse ed 2 cm in o
he dis al colon on pos na al Day 10.
Con ols: saline. G oup gas ic
in amma ion: 0.2 mL 0.1% IA in 2%
suc ose daily by o al ga age once
pe day om 10 o 15 pos na al days.
Con ols: 2% suc ose
EMG o ac omio apezius. A g ea e
isce omo o esponse was obse ed
a 6–8 weeks a e neona al
in amma o y colon insul o pups,
emaining hype sensi i e a leas a e
12 weeks. Adul a s who ecei ed he
colonic insul a 6–8 weeks old did no
show inc eased EMG ac i i y o GD
a e 6–8 weeks. Gas ic i i a ion in
a pups wi h IA inc eases EMG
ac i i y o GD in adul li e
Daily in a hecal adminis a ion o he
kB- ecep o an agonis kB-Fc (5 μg
in 10 μL s e ile saline o ehicle) o
5 days, signi can ly supp essed he
EMG esponse o gas ic dis ension in
he unc ional dyspepsia g oup. NGF
neu alizing an ibody (16 μg/kg o
5 days) diminished he EMG esponse
o GD in a s wi h unc ional dyspepsia
Dec ease o K
1.1 ion channel
exp ession in DRG neu ons inc eases
EMG esponse o GD in na¨
ı e a s.
T ea men wi h an agonis o
glucoco icoid ecep o s (16 μg/kg o
RU-486) om pos na al days 9–17 did
no show inc eased EMG ac i i y o
GD in adul hood. In ape i oneal
adminis a ion o ad ene gic- ecep o
an agonis s, 2 mg/kg phen olamine,
2 mg/kg p op anolol, and 2 mg/kg
CL316243, daily o 5 days, diminishes
EMG esponse o GD in a s wi h
unc ional dyspepsia
Sun e al., 2014
[34] 45 male Sp ague–Dawley a s
GD by in agas ic balloon. Mul iple
small ulce s we e p oduced by
injec ing 100 μL o 20% ace ic acid
in o 20 si es in he submucosal laye
o he s omach
EMG o ac omio apezius. GD o 20,
40, 60, and 80 mmHg p oduced
inc easing EMG ac i i y
Gas ic elec ic s imula ion wi h a ain
on o 0.1 s and o 0.4 s, 0.25 ms,
100 Hz, and 6 mA signi can ly
educed EMG esponses a GD 40, 60,
and 80 mmHg
Naloxone blocked he inhibi o y e ec
o gas ic elec ic s imula ion
Zhou e al.,
2017 [36]
24 male neona al
Sp ague–Dawley a s (7 days old)
GD by in agas ic balloon. Te
unc ional dyspepsia g oup was
ga aged wi h 0.2 mL o 0.1% IA in
2% suc ose daily o 6 days.
Con ols: 2% suc ose. When he a s
we e 8 weeks old, acu e s ess was
also p oduced by placing he a s o
90 min in a cylind ical plas ic ube o
60 mm diame e and 150 mm leng h
EMG o ac omio apezius. Ra s which
su e ed om neona al unc ional
dyspepsia showed inc eased EMG o
40, 60, and 80 mmHg GD a week 8.
Acu e es ain s ess inc eased EMG
esponses in a s wi h neona al
unc ional dyspepsia and in he
con ol a s, wi h highe ac i i y in
he neona al dyspep ic a s a 60 and
80 mmHg
P e en i e and cu a i e
elec oacupunc u e in he ibia and
head o he bula wi h a ain on o
0.1 s and o 0.4 s, 0.3 ms, 100 Hz, and
1 mA educed EMG esponses o GD
Ad eno ecep o blocking d ugs
(p opanolol and phen olamine)
a oided EMG esponses o s ess
In e na ional Jou nal o Clinical P ac ice 7
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Table 1: Con inued.
Au ho , yea Sample Gas ic insul Elec omyog aphy Te apeu ic o
inhibi o y p ocedu e O he s
Li e al., 2017
[30]
14 male 6-week-old
Sp ague–Dawley a s
GD by in agas ic balloon.
Co icos e one injec ion (5 mg/kg)
EMG o ac omio apezius.
Co icos e one injec ion p oduced
gas ic hype sensi i i y o heal hy
a s, showing inc eased EMG ac i i y
a 20, 40, 60, and 80 mmHg GD a e
co icos e one injec ion, compa ed
wi h p einjec ion
GF109203X (inhibi o o p o ein
kinase C) blocked he hype exci abili y
induced by co icos e one injec ion.
H89 (inhibi o o p o ein kinase A)
had no ob ious e ec on EMG
ampli ude
Co icos e one did no al e he hind p
and wi hd awal h eshold. Te e ec
induced by co icos e one is isce al
pain speci c
Dong e al.,
2019 [25]
30 male neona al
Sp ague–Dawley a s (10 days
old)
Te unc ional dyspepsia g oup was
ga aged wi h 0.2 mL o 0.1% IA in
2% suc ose daily o 6 days.
Con ols: 2% suc ose. GD by
in agas ic balloon. All
expe imen s we e pe o med when
he a s we e adul s (8–11 weeks old)
EMG o ac omio apezius. Responses
we e highe in he unc ional
dyspepsia g oup a 60, 80, and
100 mmHg GD in espec o con ols
An ine e g ow h ac o he apy only
imp o ed he EMG esponse in
con ol a s a 100 mmHg o GD, while
in dyspep ic a s, i diminished EMG
ac i i y a 40, 60, 80, and 100 mmHg.
Elec ic gas ic s imula ion (mino
cu a u e o gas ic an o and se osa;
0.25 s on and 0.25 o ; 100 Hz; 0.25 ms;
6 mA) no malized EMG esponses
Naloxone and an agonis s o opioid
ecep o s blocked he e ec o he
elec ic gas ic s imula ion
Wang e al.,
2020 [38]
20 p egnan Sp ague–Dawley
a s and hei adul male
o sp ing (6 weeks old)
P ena al ma e nal s ess du ing
p egnancy by in e mi en s ess
p o ocol (wa e a oidance s ess,
cold es ain s ess, and o ced
swimming s ess). Con ols: Sham
ma e nal s ess. GD o he o sp ing
by in agas ic balloon
EMG o ac omio apezius. A 6 weeks
old, esponses we e highe in
o sp ing om p ena al ma e nal
s ess g oup a 60, 80, and 100 mmHg
GD in espec o he o sp ing om
p ena al ma e nal sham s ess
Amilo ide (blocke o acid-sensing ion
channels) in a hecally injec ed
diminishes EMG esponse in
a dose-dependen manne (1, 3, and
10 μg in 10 μL) a 60–100 mmHG
compa ed wi h saline
LV-p65 shRNA in a hecal injec ion
esul ed in a d ama ic educ ion in
EMG esponses a 60–100 mmHg
Ouyang e al.,
2020 [32]
52 male neona al
Sp ague–Dawley a s (10 days
old)
Te unc ional dyspepsia g oup was
ga aged wi h 0.2 mL o 0.1% IA in
2% suc ose daily o 6 days.
Con ols: 2% suc ose. GD by
in agas ic balloon. All
expe imen s we e pe o med when
he a s we e adul s (10 weeks old)
EMG o ac omio apezius. Responses
we e highe in unc ional dyspepsia
g oup a 40, 60, and 80 mmHg GD in
espec o con ols
Elec oacupunc u e (0.3 ms, 100 Hz,
and 0.1 mA; 45 min pe day o a week)
in poin ST36 ( ibia) educed EMG
esponses o GD (40, 60, and
80 mmHg) compa ed o s imula ion in
nonacupunc u e poin s
Ad eno ecep o blocking d ugs
(p opanolol and phen olamine)
diminished EMG esponses o GD 40,
60, and 80 mmHg
Han e al.,
2021 [26]
42 male neona al
Sp ague–Dawley a s (10 days
old)
GD by in agas ic balloon. Te
unc ional dyspepsia g oup su e ed
s ess ( ail clamping) and was gi en
0.2 mL o 0.1% IA in 2% suc ose
daily o 6 days. Con ols: 2%
suc ose
EMG o ac omio apezius. A 8 weeks
old, esponses we e highe in
unc ional dyspepsia g oup a
40–60 mmHg GD in espec o
con ols
No ulce s o bleeding we e e iden in
he gas ic and duodenal mucosa in FD
a s
No e: AOAA, aminooxyace ic acid (CBS inhibi o ); CBS, cys a hionine-β-syn he ase enzyme; CTOP, D-Phe-Cys-Ty -D-T p-O n-T -Pen-T -NH2 (opioid ecep o an agonis ); EMG, elec omyog aphy; ERK1/
2, ex acelula signal- egula ed p o ein kinase 1/2, IA: iodoace amide; STZ: s ep ozo ocin.
Abb e ia ions: DRG, do sal oo ganglia; GD, gas ic dis ension; NGF, ne e g ow h ac o ; kB: opomyosin- ela ed kinase B; TRPA1, ansien ecep o po en ial A1.
8In e na ional Jou nal o Clinical P ac ice
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pain and igge ing e e en ac i i y o he neck muscles, wi h
he accesso y ne e also in ol ed [52]. Fu he mo e, he
s omach is also sensi i ely supplied by he splanchnic ne es,
om ho acic le els, hus allowing epigas ic and/o in e -
scapula pain and spinal spasm and a ching, which a e e-
ac ions obse ed in mo e se e e agg essions [25, 31]. Spinal
a e en pa hways a e in ol ed in mechanic gas ic ha m, while
agal a e en pa hways pa icipa e in he mal and chemical
gas ic nocicep ion [24, 27, 28, 33, 53–55].
4.3. Clinical Implica ions. Ou esul s migh con ibu e o
explain equen clinical si ua ions o neck pain since he
e iewed s udies we e pe o med in models o e y p e alen
diso de s such as gas ic in amma ion, unc ional dyspepsia,
me abolic synd ome, s ess, gas ic ulce s, o colon
in amma ion.
Also, gas ic dis ension was pe o med in e e y single
case, so hese esul s mus be conside ed in mos pa ien s
wi h obesi y since gas ic dila a ion is a common ea u e
[56, 57] and obesi y is ela ed o neck pain [58, 59].
In his sense, neck pain is associa ed o diges i e dis-
o de s and smoking [60], and smoking is known o i i a e
he esophagus and s omach [61, 62]. Mo eo e , me abolic
synd ome [63] and diabe es [64–67] a e also ela ed o neck
pain, and diabe es is known o cause isce al hype sensi i i y
[11, 12], also in he s omach [22], diminishing i s h eshold
o igge neck spasm.
Neck pain is also associa ed o s ess [68, 69], which has
shown o igge apezius muscle spasm [70]. S ess is
equen ly pe cei ed in he neck [71, 72] and/o in he
epigas ic a ea [5, 43]. Fu he mo e, co isol especially in-
c eases isce al pain sensi i i y bu no soma ic. I is no
a nonspeci c o oxic e ec [30, 73]. Te acu e s ess causes
isce al esponses mo e o en and ea lie han soma ic e-
sponses [30]. So, a pain in he neck due o s ess ul si ua ions
would no be di ec ly due o soma ic issues bu media ed by
he isce al hype sensi i i y. Tus, he gas ic a e en
pa hway is sensi ized in s essed subjec s by co isol, and
some pa ien s migh pe cei e i in he epigas ic a ea and
some o he migh pe cei e i in he neck, as isce al e e ed
pain. I is u he in e es ing o no e ha he e ec o co isol
Rouzade e al. [23]
Ozaki e al. [33]
Lamb e al. [28]
Lamb e al. [29]
Kang e al. [27]
Liu e al. [31]
Kondo e al. [24]
Zhang e al. [22]
Wins on and Sa na
[35]
Sun e al. [34]
Zhou e al. [36]
Li e al. [30]
Dong e al. [25]
Ouyang e al. [32]
Wang e al. [38]
Han e al. [26]
Sequence gene a ion (selec ion bias)
Baseline cha ac e is ics (selec ion bias)
Alloca ion concealmen (selec ion bias)
Random housing (pe o mance bias)
Blinding (pe o mance bias)
Random ou come assessmen (de ec ion bias)
Blinding (de ec ion bias)
Incomple e ou come da a (a i ion bias)
Selec i e ou come epo ing ( epo ing bias)
O he bias
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?? ? ?? ?
? ? ? ? ? ? ? ? ? ?
?? ? ? ? ? ? ? ?? ?
?? ? ? ? ? ? ? ? ? ? ? ??
? ? ? ? ? ??? ? ? ?? ? ?
????? ? ? ? ? ? ? ? ???
??? ? ????????
? ?
+
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Low isk
High isk
Unclea isk
Figu e 2: SYRCLE’s isk-o -bias summa y.
In e na ional Jou nal o Clinical P ac ice 9
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