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

Review Article Idiopathic Neck Pain or Neck Pain of Gastric Origin? A Systematic Review of Rat Experimental Studies on Gastric Harm Pathophysiology and Therapy ´ Angel Oliva-Pascual-Vaca , 1 , 2 , 3 Ignacio Navarro-Carmona , 2 , 3 Jes´ us Oliva-Pascual-Vaca , 1 , 2 , 3 Inmaculada Riquelme , 4 , 5 , 6 Luis Gabriel Luque-Romero , 7 , 8 and Jos´ eManuel L´ opez-Mill´ an 9 ,10 1 Instituto de Biomedicina de Sevilla-IBiS, Hospitales Universitarios Virgen del Roc´ıo y Macarena, CSIC, Universidad de Sevilla, Seville, Spain 2 Departamento de Fisioterapia, Facultad de Enfermer´ ıa, Fisioterapia y Podolog´ ıa, Universidad de Sevilla, Seville, Spain 3 Escuela de Osteopat´ıa de Madrid, Madrid, Spain 4 Research Institute on Health Sciences (IUNICS), University of Balearic Islands, Palma de Mallorca, Spain 5 Department of Nursing and Physiotherapy, University of Balearic Islands, Palma de Mallorca, Spain 6 Health Research Institute of the Balearic Islands (IdISBa), Palma 07010, Spain 7 Unidad de Investigaci´ on, Distrito Aljarafe y Sevilla Norte, Servicio Andaluz de Salud, Seville, Spain 8 Departamento de Medicina Preventiva y Salud P´ ublica, Facultad de Medicina, Universidad de Sevilla, Seville, Spain 9 Departamento de Anestesiolog´ ıa y Medicina Del Dolor, Hospital Universitario Virgen Macarena, Seville, Spain 10 Departamento de Cirug´ıa, Universidad de Sevilla, Seville, Spain Correspondence should be addressed to Ignacio Navarro-Carmona; [email protected] Received 3 December 2024; Accepted 18 April 2025 Academic Editor: Woon-Man Kung Copyright ©2025 ´ Angel Oliva-Pascual-Vaca et al. International Journal of Clinical Practice published by John Wiley & Sons Ltd. Tis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Background: Most cases of neck pain are classifed as nonspecifc or idiopathic pain and show characteristics such as sensitization, hyperalgesia, limited range of motion, and muscle spasm. Visceral disorders can trigger all those features, and gastric disorders are related to neck pain. Furthermore, stress and anxiety are frequently somaticized as neck pain. However, its pathophysiological link has never been determined. Objectives: To identify the electromyographic and postural response to experimental gastric insult in rats. Methods: A systematic review was undertaken. Searches were conducted in the PubMed and Web of Science databases. Te date of publication was not limited. References from included articles were assessed. Te sample, experimental intervention, and the results were retrieved from each study. Results: Sixteen studies were included. Acromiotrapezius muscle showed the highest activity to gastric damage, being up to 8–10 times higher than abdominal muscles contraction. Also, a postural response compatible with neck muscles spasm was observed. Te threshold for reaching cervical spasm was lowered by the addition of stress, gastritis, dyspepsia, ulcers, diabetes, or infammation of the colon. Increased visceromotor response persisted even more than 60 days after gastric insult, despite no obvious injury was already visible in the stomach. Furthermore, prenatal or neonatal gastric injury also produced gastric hypersensitivity and increased trapezius spasm in adult rats. On the contrary, neck spasm was reduced by reversing diabetes or blocking the gastric receptors and its aferent pathways. Conclusions: Gastric harm triggers neck muscles spasm. Since many gastric conditions and hypersensitivity are common and tend to be chronic, this may contribute to explain the persistence of neck pain and sensitization in many patients. Prenatal and neonatal gastrointestinal sufering increases trapezius visceromotor response in adults. Furthermore, our fndings might contribute to explain why stress is frequently somaticized as neck pain. Keywords: anxiety; diabetes; electromyography; functional dyspepsia; neck pain; peptic ulcer; psychological stress; stomach Wiley International Journal of Clinical Practice Volume 2025, Article ID 8835586, 14 pages https://doi.org/10.1155/ijcp/8835586 1. Introduction Neck pain has a high impact in society, with a prevalence of 27.0 per 1000 inhabitants in 2019 [1]. It is more common in women [2], and it constitutes the fourth cause of disability, with a cost of 134 million USD if added to low back pain [1]. When a pathoanatomical cause has been diagnosed, patients are categorized as sufering specifc neck pain, such as a chronic rheumatic disease [3], facet joint pain [4], disc herniation [5] or radiculopathy [6]. However, most cases are classifed as nonspecifc because the etiology has not been determined [7]. More than 40% of worldwide population sufers from functional gastrointestinal disorders [8]. Regarding functional dyspepsia, it results from a combination of visceral hypersensitivity, gastric motor dysfunction, and psychological issues [9], and its prevalence ranges between 7% and 34.2% around the world. Most epidemiological studies did not fnd between-sex diferences in prevalence data, but some others reported a higher ratio in female population [10]. Moreover, metabolic disorders cause visceral hypersensitivity [11, 12], which facilitates the development of gastrointestinal disorders. Tus, 75% of diabetes mellitus patients show digestive issues [13]. Regarding other gastric disorders, the prevalence of peptic ulcer in the world is 8.4% [14], while in 2019, there were 783.95 million cases of gastroesophageal refux globally, with increasing prevalence of 77.53% between 1990 and 2019 [15]. Skeletal muscles are responsible for providing support and stability to the body, as well as enabling movement. In addition, they are also involved in protecting the body against injury. In response to tissue sufering, skeletal muscles exhibit refex contraction activity as a protective mechanism that helps to prevent further damage to the afected structure by means of the adoption of a certain posture and limiting the movement of that area [16]. For instance, those muscles whose contraction protects the nerves are progressively recruited in a refex manner as the stress increases in the neural tissues [17]. Tis way, patients with disc herniation and sciatica tend to present muscular contracture which usually is accompanied by a characteristic antalgic posture [18]. Tis kind of activity has been observed not only in the case of somatic tissues but also for visceral ones. Tus, it is generally well known that kidney disorders tend to produce hypertonus in lumboabdominal muscles [16]. Another example could be the abdominal spasm in peritonitis. However, the musculoskeletal spasm which is generated because of gastric sufering is not so well recognized [19]. Tus, it seems interesting to determine which is the musculoskeletal contracture because of stomach disorders. Te aim of this study is to systematically review studies that analyze the electromyographic and postural response to experimental gastric insult and/or distress in rats. 2. Material and Methods Tis systematic review has been performed according to the Preferred Reporting Item for Systematic Reviews and MetaAnalyses (PRISMA) guidelines [20]. It was registered in the International Prospective Register of Systematic Reviews (PROSPERO), with registration number CRD42022362341. 2.1. Search Strategy. Two authors conducted the search between November 9 th 2022 and January 9 th 2023 using the PubMed and Web of Science databases. Te search strategy used was (electromyograph ∗ OR postur ∗ ) AND (gastric ∗ OR gastro ∗ OR digestiv ∗ OR stomach ∗ ) AND (rat OR rats OR mouse OR mice) NOT gastrocnemi ∗ . Te date of publication was not limited. Reference lists were checked to include any other article that met the characteristics sought. In case of disagreements, a third researcher solved the issue. 2.2. Selection Criteria. We included studies about the electromyographic and/or postural consequences of experimental gastric distress in rats and mice, published either in Spanish or English. Te selection of articles was carried out by two researchers according to the inclusion and exclusion criteria. Disagreements were solved by another researcher. 2.3. Data Extraction and Methodological Quality Assessment. Te bibliographical reference, sample, experimental intervention, and results were retrieved from each study. Furthermore, a modifed version of the Systematic Review Center for Research for Laboratory Animal Experimentation (SYRCLE) [21] risk of bias tool was used to assess the methodological quality of the selected articles. Tis instrument assesses the risk of bias of animal intervention studies, thus scoring the internal and external validity. All this information was collected by two researchers following standardized forms, and disagreements were resolved by another researcher. 3. Results From the literature search, 1181 studies were identifed. After reading titles and abstracts, and after considering the ‘cited-by’ references, 227 full-text articles were assessed for eligibility, with fnally 16 studies included in the systematic review. Figure 1 shows the fow diagram. 3.1.Sample. A total of 789 rats were included in the reviewed studies, with 44 being female Sprague–Dawley [22], 32 male Wistar [23], and 713 male Sprague–Dawley. 3.2. Gastric Harm. As an injury to the stomach, all the studies performed gastric distension with an intragastric balloon. In some studies, that was the unique harm applied to the animals [23, 24]. In other investigations, chemical or metabolic insult was further induced [22, 25–36]. Tus, the studies used HCl [28] or acetic acid [27–29, 33, 34] to produce gastric ulcers or iodoacetamide to cause gastritis [25, 26, 28, 29, 31–33, 35, 36]. In addition to cause functional dyspepsia to the rats by using iodocetamide, further gastric 2International Journal of Clinical Practice ijclp, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Labtiva Inc.), Wiley Online Library on [20/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License harm was obtained stressing the rats, either placing them in a small cylindric tube [36] or clamping their tails [26]. Another study achieved gastric hypersensitivity by injecting corticosteroids [30], while other did so by inducing diabetes through streptozotocine injection [22]. One study assessed gastric hypersensitivity after chemical infammatory insult to the distal colon by means of trinitobenzene sulfonic acid [37]. Finally, another study induced prenatal maternal stress and tested the gastric hypersensitivity of the ofspring by gastric distension in adulthood [38]. 3.3. Prenatal and Neonatal Gastric Injury. Six studies performed gastric injury (functional dyspepsia model) when the rats were newborn, from one to ten days old [25, 26, 31, 32, 35, 36] and assessed the consequences when the rats were adults (6–12 weeks old), showing also enhanced visceromotor response. One of those investigations did no direct gastric injury but did colon infammation during frst days of life, resulting similarly in adult gastric hypersensitivity and neck spasm [35]. 3.4. Postural Response. Te observed reactions from 15 mmHg of gastric distension were raising and turning on both sides of the head, corresponding to contractions of the neck muscles [23]. Tis reaction was also described as brief head movement followed by immobility [31]. As gastric injury increases, abdominal muscles contracted, followed by abdominopelvic lifting and stretching of body [25, 31]. Further gastric harm by 6 days of oral gavages with iodoacetamide enhanced the postural responses to gastric distension at 8 weeks compared with controls [31]. Records identified from: Databases (n = 1667) PubMed (n = 450) Web of Science (n = 1217) Records removed before screening: Duplicate records removed (n = 383) Other languages (n = 103) Records marked as ineligible by automation tools (n = 0) Records removed for other reasons (n = 0) Records screened (n = 1181) Records sought for retrieval (n = 224) Records not retrieved (n = 0) Full-text articles assessed for eligibility (n = 227) Studies included in the review (n = 16) Identification Screening Included Records excluded (n = 957): Not study electromyography or posture (n = 387) Other viscera (n = 423) Not experimental studies (n = 99) Study of more than one viscera (n = 48) Reports from references lists (n = 3) Records excluded (n = 211): Not study electromyography or posture (n = 37) Other viscera (n = 74) Study of more than one viscera (n = 56) Not report electromyographic data (n = 12) Figure 1: PRISMA fowchart of the study selection process. PRISMA, preferred reporting items for systematic reviews and meta-analyses. ∗ Consider, if feasible to do so, reporting the number of records identifed from each database or register searched (rather than the total number across all databases/registers). ∗∗ If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools. From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hofmann TC, Mulrow CD, et al. Te PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71. For more information, visit: https://www.prisma-statement.org/. International Journal of Clinical Practice 3 ijclp, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Labtiva Inc.), Wiley Online Library on [20/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 3.5. Electromyographic Response. Te 16 studies included in this review assessed the muscular activity in the neck as a method to record if gastric injury had been achieved. All the 16 studies registered an increase in neck muscles contraction because of experimentally developed gastric harm. Te most ancient of the studies states that their preliminary observations showed that gastric distension in rats did not induce abdominal contractions, as did colorectal distension, but raised the head and stretching of the body [23]. Tus, they placed the electrodes in the neck muscles, with no further information about the specifc location. After that, Ozaki et al. [33] evaluated the electromyographic response in the rectus abdominus, external oblique, acromiotrapezius, spinotrapezius, and sternomastoideus. Te highest contraction response was found in acromiotrapezius, followed by spinotrapezius and sternomastoideus. Acromiotrapezius showed up to 8–10 times higher levels of contraction compared with abdominal muscles and spinotrapezius and sternomastoideus up to doubled abdominal activity. From then on, all of the 14 studies registered the electromyographic response in the acromiotrapezius muscle. Mechanic distension of the stomach has proven to trigger neck spasm by its own [23, 24]. A lower gastric distension is needed to achieve the same neck electromyographic response in the case of adding stress [36], a chemical injury to cause gastric ulcers [27–29, 33, 34] or gastritis [25, 28, 31–33, 35, 36], or metabolic injury to cause visceral hypersensitivity by diabetes [22]. 3.6. Terapeutic Interventions. Some of the studies tested therapeutic or inhibitory procedures, such as morphine sulfate [23], splanchnic nerve resection, vagotomy [34, 38], chemical denervation with capsaicin [28], inhibitors of ion channels of gastric aferent primary neurons [24, 35, 38], nerve growth factor neutralization [25, 29, 35], blocking of brain-derived neurotrophic factor in the dorsal root ganglia [35], gastric electric stimulation [25, 34], electroacupuncture [32, 36], adrenoreceptor antagonists (propranolol and phentolamine) [32, 35, 36], antagonists of glucocorticoid receptors [35], the inhibition of the consequences of diabetes by means of aminooxyacetic acid, and inhibitors of protein kinase A and C, to inhibit the efects of corticosteroids [30]. All of these procedures for the treatment of the stomach or its aferents pathways implied a reduction in neck spasm in all of the studies, with the only exception of inhibitors of protein kinase A [30]. Also, splanchnic nerve resection avoided the neck spasm during mechanical insult but not during chemical insult [28]. On the contrary, vagotomy avoided it during chemical aggression but not during mechanical harm [24]. Furthermore, some interventions were performed to block the therapeutic efects. Tus, neck muscles spasm increased by the application of antagonists of opioid receptors such as naloxone [23, 25, 34] and CTOP [25]. To fnish with, the K v 1.1 ion channel seems to be also involved in the inhibition of this visceromotor response since the decrease in the expression of this ion channel in DRG neurons increases EMG response to GD [35]. Table 1 summarizes the studies (Table 1). 3.7. Risk-of-Bias Assessment. In most studies, multiple riskof-bias domains were assessed as unclear due to poor reporting of study methodology. Four studies (25%) reported groups with similar baseline characteristics, while all but one of the remaining studies was assessed as unclear. Only one study used some form of random selection during outcome assessment, and there was some form of blinding in four studies (25%). However, the risk of attrition bias was high in only two studies (12.5%). All studies were assessed as presenting low risk for selective outcome reporting and none of them were assessed as high risk for other biases (Figure 2). 4. Discussion 4.1. Electromyographic and Postural Response. Our aim was to analyze the electromyographic and postural response to experimental gastric injury in rats. According to our results, the main muscle spasm occurs in the neck, especially in the acromiotrapezius muscle, triggering postural neck consequences such as raising and turning the head, or neck immobility. Increasing gastric harm triggers abdominal muscles contracture, body stretching, and spine arching [31]. It is interesting to note that this neck spasm happened in every single study. In fact, it seems that it happens in every single rat since no author declares that some rats do not show that activity if damage is present. So, our results show that the neck somatization is the rule in gastric sufering. Our fndings in experimental studies of gastric harm agree with those clinically observed in human population sufering torticollis caused by gastroesophageal refux. It is known as Sandifer syndrome, and it is usually misdiagnosed [39, 40]. It presents neck spasm and even spine arching in severe cases. Te pathophysiological basis is thought to be a protective viscerosomatic refex to avoid aspiration of the gastric content and contribute to empty the esophagus [39, 41]. Tese somatic consequences of visceral disorders are generally well known for structures such as the kidney [16]. Clinicians and patients use to detect quite well when the lumbar spasm, hypersensitivity, and protective posture is the consequence of renal sufering, such as in the case of nephrolithiasis. However, they do not recognize it in the case of gastric disorders and neck pain [19]. As previously exposed, 90% of neck pain are classifed as nonspecifc, mechanical, or idiopathic. Tey are characterized by pain, sensitization, hyperalgesia, muscle hypertonus, and limited range of motion [42]. All these features can be a consequence of a visceral disorder [16, 43]. 4.2. Aferent Pathways. Visceral pain is referred to somatic areas known as head zones [44]. Te visceral referred pain, and secondary hyperalgesia, occurs in areas neuromerically connected to the organ [45, 46]. In the case of the stomach, the head zones are the neck, the epigastric, and the interscapular area [47]. Te phrenic nerves (C3–C5) are known to supply the stomach [48–51] and so does the vagus nerve. Tus, the aferent discharge sensitizes the upper central nervous system, causing 4International Journal of Clinical Practice ijclp, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Labtiva Inc.), Wiley Online Library on [20/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Table 1: Synthesis of the included studies. Author, year Sample Gastric insult Electromyography Terapeutic or inhibitory procedure Others Rouzade et al., 1998 [23] 32 male Wistar rats GD by intragastric balloon EMG of the neck muscles. A total of 15 or 20 mmHg GD: EMG activity increased between 192% and 705%. When the distension procedure was repeated 2, 4, and 7 days after the frst one, the pain threshold was not diferent in respect to the frst day 4 mg/kg of intraperitoneal morphine sulfate signifcantly increased pain threshold 2.5 mg/kg of naloxone reversed the efects of morphine Ozaki et al., 2002 [33] 83 male Sprague–Dawley rats GD by intragastric balloon in the three groups. Group 1: multiple small ulcers were produced by injecting 10 μL of 20% acetic acid into 20 sites in the submucosal layer of the stomach. Group 2: a single injection of 30 μL of 20% acetic acid producing a single ulcer. Controls: Identical injection of sterile saline. Group 3: drinking water with IA 0.1% to produce gastritis. Control group: water with the same pH EMG of acromiotrapezius, spinotrapezius, sternomastoideus, rectus abdominus, and external oblique muscles. From 40 mmHg GD, acromiotrapezius EMG activity increased more than 400%. Spinotrapezius and sternomastoideus EMG increased more than 100%. Abdominal muscles barely responded. Rats with multiple ulcers increased response from 10 mmHg GD up to 60 days after injury. Rats with a single ulcer showed modest increased response but did not difer from controls. Rats treated with IA increased response from 40 mmHg GD 7 days after beginning the injury Increased visceromotor response persisted for 60 days after acetic acid treatment in spite that ulcers had healed, proved by macroscopic and histological assessment. However, gastric infammation was still present according to myeloperoxidase activity. Normal stomachs 60 days after limited (7 days) IA exposure did not show increased visceromotor response International Journal of Clinical Practice 5 ijclp, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Labtiva Inc.), Wiley Online Library on [20/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Table 1: Continued. Author, year Sample Gastric insult Electromyography Terapeutic or inhibitory procedure Others Lamb et al., 2003 [28] 56 male Sprague–Dawley rats GD by intragastric balloon. Instillation of 750 μL of 0.05, 0.15, or 0.3 mol/L of HCl. Controls: instillation of 750 μL sterile saline. Group 1: injection of 100 μL 60% acetic acid to produce an ulcer. Controls: injection of 100 μL of sterile saline. Group 2: drinking water with IA 0.1% for 5 days to produce gastritis. Controls: water with the same pH EMG of acromiotrapezius. Instillation of saline did not change EMG activity but 0.15 and 0.3 mol/L of HCl increased visceromotor response at 2 min and remained elevated for 30 min in spite that no macroscopic lesions were seen and submucosa was histologically intact. However, there were occasional red blood cells adhered to the gastric epithelium and dilated vessels. One hour after administration of 0.15 or 0.3 mol/L HCl, the visceromotor response had decreased to 87% ±11% of control. IA increased EMG activity in spite that it did not cause macroscopic lesions. Saline did not trigger visceromotor responses in rats with gastric ulcers, but 0.05 mol/L HCl increased EMG activity Vagotomy did not alter the response to mechanical stimulation but blunted the chemical stimulation. On the contrary, splanchnic nerve resection blunted mechanical stimulation but did not afect the visceromotor response to acid stimulation. Chemical denervation by capsaicin also suppresses the visceromotor response to chemical injury. In presence of ulcers, vagotomy signifcantly blunted the EMG response to HCl compared with splanchnic nerve resection Lamb et al., 2003 [29] 28 male Sprague–Dawley rats GD by intragastric balloon. Injection of 100 μL 60% acetic acid to produce kissing ulcers. Controls: injection of 100 μL of sterile saline EMG of acromiotrapezius. Ulcers increase visceromotor response Neutralizing NGF antibodies injection diminished gastric infammation and visceromotor response Kang et al., 2005 [27] 25 male Sprague–Dawley rats GD by intragastric balloon. Intraluminal injection of 100 μL 60% acetic acid to produce kissing ulcers. Controls: injection of 100 μL of sterile saline EMG of acromiotrapezius. GD triggered increased EMG activity for at least 14 days in the experimental group even when the initial injury was healed. After 6 weeks, no macroscopic lesions were observed and no diferences to GD were found between groups Infammation directly alters gastric sensory and motor function. Increased activation of aferents triggers vagovagal refexes Liu et al., 2008 [31] 10 male neonatal Sprague–Dawley rats (1 day old) GD by intragastric balloon. Mild transient infammation of the surface epithelium of the gastric mucosa by 0.2 mL 0.1% IA in 2% sucrose daily by oral gavages for 6 days. Controls: 2% sucrose EMG of acromiotrapezius. After 8 weeks, compared with controls, rats with gastric irritation exhibited signifcant increases in EMG activity at GD pressures of 60 (196.1% vs. 147.5%) and 80 mmHg (271.2% vs. 205.5%). A trend toward an increase was also seen at 40 mmHg (141.9% vs. 112.1%) Gastric irritation in the neonatal period can result in chronic gastric hypersensitivity in adults even in the absence of signifcant detectable gastric pathology 6International Journal of Clinical Practice ijclp, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Labtiva Inc.), Wiley Online Library on [20/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Table 1: Continued. Author, year Sample Gastric insult Electromyography Terapeutic or inhibitory procedure Others Kondo el al., 2009 [24] 152 male Sprague–Dawley rats GD by intragastric balloon. Controls: rats without stimulation EMG of acromiotrapezius. 60 mmHg of GD led to an increase in acromiotrapezius EMG activity Intrathecal injection of TRPA1 antisense reduced visceromotor response and suppressed ERK1/2 activation in the dorsal root ganglion but not in the nodose ganglion. Intrathecal and intraperitoneal injections of the TRPA1 inhibitor HC-03003 suppressed the response to noxious GD Splanchnic nerve bilateral resection signifcantly reduced the visceromotor response to GD whereas subdiaphragmatic vagotomy did not difer from sham-operated rats Zhang et al., 2013 [22] 44 female Sprague–Dawley rats GD of 60–120 mmHg by intragastric balloon. A single intraperitoneal injection of STZ to induce diabetes mellitus, in order to generate gastric hypersensitivity. Controls: solvent (citrate bufer) EMG of acromiotrapezius. Diabetic rats showed increased EMG activity at pressures of 60, 80, 100, and 120 mmHg CBS inhibitor AOAA (5 and 10 mg/kg) treatment diminishes acromiotrapezius EMG response to GD Epigenetic regulation might be involved in the development of gastric hypersensitivity by enhancing nuclear factor-kB-mediated CBS gene expression Winston and Sarna, 2013 [35] 132 male Sprague–Dawley adult rats and 10-day-old pups GD of 30–120 mmHg by intragastric balloon. Group colon infammation: adults and pups received 0.2 mL of 130 mg/kg trinitobenzene sulfonic acid in 10% ethanol in saline through a tube inserted 2 cm into the distal colon on postnatal Day 10. Controls: saline. Group gastric infammation: 0.2 mL 0.1% IA in 2% sucrose daily by oral gavage once per day from 10 to 15 postnatal days. Controls: 2% sucrose EMG of acromiotrapezius. A greater visceromotor response was observed at 6–8 weeks after neonatal infammatory colon insult of pups, remaining hypersensitive at least after 12 weeks. Adult rats who received the colonic insult at 6–8 weeks old did not show increased EMG activity to GD after 6–8 weeks. Gastric irritation in rat pups with IA increases EMG activity to GD in adult life Daily intrathecal administration of the trkB-receptor antagonist trkB-Fc (5 μg in 10 μL sterile saline or vehicle) for 5 days, signifcantly suppressed the EMG response to gastric distension in the functional dyspepsia group. NGF neutralizing antibody (16 μg/kg for 5 days) diminished the EMG response to GD in rats with functional dyspepsia Decrease of K v 1.1 ion channel expression in DRG neurons increases EMG response to GD in na¨ ıve rats. Treatment with antagonist of glucocorticoid receptors (16 μg/kg of RU-486) from postnatal days 9–17 did not show increased EMG activity to GD in adulthood. Intraperitoneal administration of adrenergic-receptor antagonists, 2 mg/kg phentolamine, 2 mg/kg propranolol, and 2 mg/kg CL316243, daily for 5 days, diminishes EMG response to GD in rats with functional dyspepsia Sun et al., 2014 [34] 45 male Sprague–Dawley rats GD by intragastric balloon. Multiple small ulcers were produced by injecting 100 μL of 20% acetic acid into 20 sites in the submucosal layer of the stomach EMG of acromiotrapezius. GD of 20, 40, 60, and 80 mmHg produced increasing EMG activity Gastric electric stimulation with a train on of 0.1 s and of 0.4 s, 0.25 ms, 100 Hz, and 6 mA signifcantly reduced EMG responses at GD 40, 60, and 80 mmHg Naloxone blocked the inhibitory efect of gastric electric stimulation Zhou et al., 2017 [36] 24 male neonatal Sprague–Dawley rats (7 days old) GD by intragastric balloon. Te functional dyspepsia group was gavaged with 0.2 mL of 0.1% IA in 2% sucrose daily for 6 days. Controls: 2% sucrose. When the rats were 8 weeks old, acute stress was also produced by placing the rats for 90 min in a cylindrical plastic tube of 60 mm diameter and 150 mm length EMG of acromiotrapezius. Rats which sufered from neonatal functional dyspepsia showed increased EMG to 40, 60, and 80 mmHg GD at week 8. Acute restraint stress increased EMG responses in rats with neonatal functional dyspepsia and in the control rats, with higher activity in the neonatal dyspeptic rats at 60 and 80 mmHg Preventive and curative electroacupuncture in the tibia and head of the fbula with a train on of 0.1 s and of 0.4 s, 0.3 ms, 100 Hz, and 1 mA reduced EMG responses to GD Adrenoreceptor blocking drugs (propanolol and phentolamine) avoided EMG responses to stress International Journal of Clinical Practice 7 ijclp, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Labtiva Inc.), Wiley Online Library on [20/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Table 1: Continued. Author, year Sample Gastric insult Electromyography Terapeutic or inhibitory procedure Others Li et al., 2017 [30] 14 male 6-week-old Sprague–Dawley rats GD by intragastric balloon. Corticosterone injection (5 mg/kg) EMG of acromiotrapezius. Corticosterone injection produced gastric hypersensitivity of healthy rats, showing increased EMG activity at 20, 40, 60, and 80 mmHg GD after corticosterone injection, compared with preinjection GF109203X (inhibitor of protein kinase C) blocked the hyperexcitability induced by corticosterone injection. H89 (inhibitor of protein kinase A) had no obvious efect on EMG amplitude Corticosterone did not alter the hind p and withdrawal threshold. Te efect induced by corticosterone is visceral pain specifc Dong et al., 2019 [25] 30 male neonatal Sprague–Dawley rats (10 days old) Te functional dyspepsia group was gavaged with 0.2 mL of 0.1% IA in 2% sucrose daily for 6 days. Controls: 2% sucrose. GD by intragastric balloon. All experiments were performed when the rats were adults (8–11 weeks old) EMG of acromiotrapezius. Responses were higher in the functional dyspepsia group at 60, 80, and 100 mmHg GD in respect to controls Antinerve growth factor therapy only improved the EMG response in control rats at 100 mmHg of GD, while in dyspeptic rats, it diminished EMG activity at 40, 60, 80, and 100 mmHg. Electric gastric stimulation (minor curvature of gastric antro and serosa; 0.25 s on and 0.25 of; 100 Hz; 0.25 ms; 6 mA) normalized EMG responses Naloxone and antagonists of opioid receptors blocked the efect of the electric gastric stimulation Wang et al., 2020 [38] 20 pregnant Sprague–Dawley rats and their adult male ofspring (6 weeks old) Prenatal maternal stress during pregnancy by intermittent stress protocol (water avoidance stress, cold restraint stress, and forced swimming stress). Controls: Sham maternal stress. GD to the ofspring by intragastric balloon EMG of acromiotrapezius. At 6 weeks old, responses were higher in ofspring from prenatal maternal stress group at 60, 80, and 100 mmHg GD in respect to the ofspring from prenatal maternal sham stress Amiloride (blocker of acid-sensing ion channels) intrathecally injected diminishes EMG response in a dose-dependent manner (1, 3, and 10 μg in 10 μL) at 60–100 mmHG compared with saline LV-p65 shRNA intrathecal injection resulted in a dramatic reduction in EMG responses at 60–100 mmHg Ouyang et al., 2020 [32] 52 male neonatal Sprague–Dawley rats (10 days old) Te functional dyspepsia group was gavaged with 0.2 mL of 0.1% IA in 2% sucrose daily for 6 days. Controls: 2% sucrose. GD by intragastric balloon. All experiments were performed when the rats were adults (10 weeks old) EMG of acromiotrapezius. Responses were higher in functional dyspepsia group at 40, 60, and 80 mmHg GD in respect to controls Electroacupuncture (0.3 ms, 100 Hz, and 0.1 mA; 45 min per day for a week) in point ST36 (tibia) reduced EMG responses to GD (40, 60, and 80 mmHg) compared to stimulation in nonacupuncture points Adrenoreceptor blocking drugs (propanolol and phentolamine) diminished EMG responses to GD 40, 60, and 80 mmHg Han et al., 2021 [26] 42 male neonatal Sprague–Dawley rats (10 days old) GD by intragastric balloon. Te functional dyspepsia group sufered stress (tail clamping) and was given 0.2 mL of 0.1% IA in 2% sucrose daily for 6 days. Controls: 2% sucrose EMG of acromiotrapezius. At 8 weeks old, responses were higher in functional dyspepsia group at 40–60 mmHg GD in respect to controls No ulcers or bleeding were evident in the gastric and duodenal mucosa in FD rats Note: AOAA, aminooxyacetic acid (CBS inhibitor); CBS, cystathionine-β-synthetase enzyme; CTOP, D-Phe-Cys-Tyr-D-Trp-Orn-Tr-Pen-Tr-NH2 (opioid receptor antagonist); EMG, electromyography; ERK1/ 2, extracelular signal-regulated protein kinase 1/2, IA: iodoacetamide; STZ: streptozotocin. Abbreviations: DRG, dorsal root ganglia; GD, gastric distension; NGF, nerve growth factor; trkB: tropomyosin-related kinase B; TRPA1, transient receptor potential A1. 8International Journal of Clinical Practice ijclp, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Labtiva Inc.), Wiley Online Library on [20/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License pain and triggering eferent activity to the neck muscles, with the accessory nerve also involved [52]. Furthermore, the stomach is also sensitively supplied by the splanchnic nerves, from thoracic levels, thus allowing epigastric and/or interscapular pain and spinal spasm and arching, which are reactions observed in more severe aggressions [25, 31]. Spinal aferent pathways are involved in mechanic gastric harm, while vagal aferent pathways participate in thermal and chemical gastric nociception [24, 27, 28, 33, 53–55]. 4.3. Clinical Implications. Our results might contribute to explain frequent clinical situations of neck pain since the reviewed studies were performed in models of very prevalent disorders such as gastric infammation, functional dyspepsia, metabolic syndrome, stress, gastric ulcers, or colon infammation. Also, gastric distension was performed in every single case, so these results must be considered in most patients with obesity since gastric dilatation is a common feature [56, 57] and obesity is related to neck pain [58, 59]. In this sense, neck pain is associated to digestive disorders and smoking [60], and smoking is known to irritate the esophagus and stomach [61, 62]. Moreover, metabolic syndrome [63] and diabetes [64–67] are also related to neck pain, and diabetes is known to cause visceral hypersensitivity [11, 12], also in the stomach [22], diminishing its threshold to trigger neck spasm. Neck pain is also associated to stress [68, 69], which has shown to trigger trapezius muscle spasm [70]. Stress is frequently perceived in the neck [71, 72] and/or in the epigastric area [5, 43]. Furthermore, cortisol especially increases visceral pain sensitivity but not somatic. It is not a nonspecifc or toxic efect [30, 73]. Te acute stress causes visceral responses more often and earlier than somatic responses [30]. So, a pain in the neck due to stressful situations would not be directly due to somatic tissues but mediated by the visceral hypersensitivity. Tus, the gastric aferent pathway is sensitized in stressed subjects by cortisol, and some patients might perceive it in the epigastric area and some other might perceive it in the neck, as visceral referred pain. It is further interesting to note that the efect of cortisol Rouzade et al. [23] Ozaki et al. [33] Lamb et al. [28] Lamb et al. [29] Kang et al. [27] Liu et al. [31] Kondo et al. [24] Zhang et al. [22] Winston and Sarna [35] Sun et al. [34] Zhou et al. [36] Li et al. [30] Dong et al. [25] Ouyang et al. [32] Wang et al. [38] Han et al. [26] Sequence generation (selection bias) Baseline characteristics (selection bias) Allocation concealment (selection bias) Random housing (performance bias) Blinding (performance bias) Random outcome assessment (detection bias) Blinding (detection bias) Incomplete outcome data (attrition bias) Selective outcome reporting (reporting bias) Other bias - - -- - - - + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ? ?? ? ?? ? ? ? ? ? ? ? ? ? ? ? ?? ? ? ? ? ? ? ?? ? ?? ? ? ? ? ? ? ? ? ? ? ?? ? ? ? ? ? ??? ? ? ?? ? ? ????? ? ? ? ? ? ? ? ??? ??? ? ???????? ? ? + - ? Low risk High risk Unclear risk Figure 2: SYRCLE’s risk-of-bias summary. International Journal of Clinical Practice 9 ijclp, 2025, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/ijcp/8835586 by Readcube (Labtiva Inc.), Wiley Online Library on [20/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License