Idiopathic Neck Pain or Neck Pain of Gastric Origin? A Systematic Review of Rat Experimental Studies on Gastric Harm Pathophysiology and Therapy

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 ijclp, 2025, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [20/05/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License 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 ijclp, 2025, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [20/05/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License 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 ijclp, 2025, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [20/05/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License 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 ijclp, 2025, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [20/05/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License 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 ijclp, 2025, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [20/05/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License 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 ijclp, 2025, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [20/05/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License 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 ijclp, 2025, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [20/05/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License 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 - - -- - - - + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ? ?? ? ?? ? ? ? ? ? ? ? ? ? ? ? ?? ? ? ? ? ? ? ?? ? ?? ? ? ? ? ? ? ? ? ? ? ?? ? ? ? ? ? ??? ? ? ?? ? ? ????? ? ? ? ? ? ? ? ??? ??? ? ???????? ? ? + - ? 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 ijclp, 2025, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [20/05/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License