{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T19:16:00Z","timestamp":1793646960537,"version":"4.5.1"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T00:00:00Z","timestamp":1675209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["81820108033"],"award-info":[{"award-number":["81820108033"]}]},{"name":"National Natural Science Foundation of China","award":["82174519"],"award-info":[{"award-number":["82174519"]}]},{"name":"National Natural Science Foundation of China","award":["CI2021A03405"],"award-info":[{"award-number":["CI2021A03405"]}]},{"name":"China Academy of Chinese Medical Sciences Innovation Fund","award":["81820108033"],"award-info":[{"award-number":["81820108033"]}]},{"name":"China Academy of Chinese Medical Sciences Innovation Fund","award":["82174519"],"award-info":[{"award-number":["82174519"]}]},{"name":"China Academy of Chinese Medical Sciences Innovation Fund","award":["CI2021A03405"],"award-info":[{"award-number":["CI2021A03405"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Transcutaneous auricular vagus nerve stimulation was recently reported to have a therapeutic potential for functional dyspepsia (FD). This study aimed to explore the integrative effects and mechanisms of auricular vagus nerve stimulation (aVNS) in a rodent model of FD. Methods: We evaluated the effects of aVNS on visceral hypersensitivity, gastric motility and open field test (OFT) activity in iodoacetamide (IA)-treated rats. The autonomic function was assessed; blood samples and tissues were collected and analyzed by an enzyme-linked immunosorbent assay and western blot. Vagotomy was performed to investigate the role of vagal efferent nerve. Results: aVNS reduced the electromyography response to gastric distension, improved gastric emptying and increased the horizontal and vertical motion scores of the OFT in IA-treated rats. The sympathovagal ratio was increased in IA-treated rats but normalized with aVNS. The serum cytokines TNF-\u03b1, IL-6, IL-1\u03b2 and NF-\u03baBp65 were increased in IA-treated rats and decreased with aVNS. The hypothalamus\u2013pituitary\u2013adrenal axis was hyperactive in IA-treated rats but inhibited by aVNS. The expression of duodenal desmoglein 2 and occludin were all decreased in IA-treated rats and increased with aVNS but not sham-aVNS. Vagotomy abolished the ameliorating effects of aVNS on gastric emptying, horizontal motions, serum TNF-\u03b1 and duodenal NF-\u03baBp65. Conclusion: aVNS improves gastric motility and gastric hypersensitivity probably by anti-inflammatory mechanisms via the vago-vagal pathways. A better understanding on the mechanisms of action involved with aVNS would lead to the optimization of the taVNS methodology and promote taVNS as a non-pharmacological alternative therapy for FD.<\/jats:p>","DOI":"10.3390\/brainsci13020253","type":"journal-article","created":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T02:21:12Z","timestamp":1675304472000},"page":"253","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Auricular Vagus Nerve Stimulation Improves Visceral Hypersensitivity and Gastric Motility and Depression-like Behaviors via Vago-Vagal Pathway in a Rat Model of Functional Dyspepsia"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3476-2452","authenticated-orcid":false,"given":"Liwei","family":"Hou","sequence":"first","affiliation":[{"name":"Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peijing","family":"Rong","sequence":"additional","affiliation":[{"name":"Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiliang","family":"Fang","sequence":"additional","affiliation":[{"name":"Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junying","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiande D. Z.","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1016\/S0140-6736(20)30469-4","article-title":"Functional dyspepsia","volume":"396","author":"Ford","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/S2468-1253(18)30003-7","article-title":"Epidemiology, clinical characteristics, and associations for symptom-based Rome IV functional dyspepsia in adults in the USA, Canada, and the UK: A cross-sectional population-based study","volume":"3","author":"Aziz","year":"2018","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/ajg.2017.154","article-title":"ACG and CAG Clinical Guideline: Management of Dyspepsia","volume":"112","author":"Moayyedi","year":"2017","journal-title":"Am. J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1080\/17474124.2019.1543586","article-title":"Postprandial distress syndrome: Stratification and management","volume":"13","author":"Carbone","year":"2019","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1111\/apt.12355","article-title":"Functional dyspepsia: The economic impact to patients","volume":"38","author":"Lacy","year":"2013","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1053\/j.gastro.2016.03.035","article-title":"Rome IV\u2014Functional GI Disorders: Disorders of Gut-Brain Interaction","volume":"150","author":"Drossman","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1053\/j.gastro.2016.02.011","article-title":"Gastroduodenal Disorders","volume":"150","author":"Stanghellini","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1136\/gutjnl-2015-310721","article-title":"Efficacy of psychotropic drugs in functional dyspepsia: Systematic review and meta-analysis","volume":"66","author":"Ford","year":"2017","journal-title":"Gut"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1111\/nmo.12760","article-title":"Modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity","volume":"28","author":"Bergmann","year":"2016","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"G700","DOI":"10.1152\/ajpgi.00426.2020","article-title":"Transcutaneous auricular vagal nerve stimulation improves functional dyspepsia by enhancing vagal efferent activity","volume":"320","author":"Zhu","year":"2021","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhou, J., Li, S., Wang, Y., Lei, Y., Foreman, R.D., Yin, J., and Chen, J.D. (2017). Effects and mechanisms of auricular electroacupuncture on gastric hypersensitivity in a rodent model of functional dyspepsia. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174568"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1056\/NEJMra1501505","article-title":"Functional Dyspepsia","volume":"373","author":"Talley","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1111\/1751-2980.12556","article-title":"Functional dyspepsia and duodenal eosinophilia: A new model","volume":"18","author":"Fan","year":"2017","journal-title":"J. Dig. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"444","DOI":"10.3904\/kjim.2016.091","article-title":"Functional dyspepsia: New insights into pathogenesis and therapy","volume":"31","author":"Talley","year":"2016","journal-title":"Korean J. Intern. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1053\/j.gastro.2008.02.093","article-title":"A Rat Model of Chronic Gastric Sensorimotor Dysfunction Resulting from Transient Neonatal Gastric Irritation","volume":"134","author":"Liu","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e13381","DOI":"10.1111\/nmo.13381","article-title":"Electroacupuncture via chronically implanted electrodes improves gastric dysmotility mediated by autonomic-cholinergic mechanisms in a rodent model of functional dyspepsia","volume":"30","author":"Zhang","year":"2018","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.2147\/NDT.S298540","article-title":"Electroacupuncture Ameliorates Depressive-Like Behaviors in Poststroke Rats via Activating the tPA\/BDNF\/TrkB Pathway","volume":"17","author":"Dong","year":"2021","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.2147\/NDT.S198804","article-title":"Borderline personality disorder, trauma, and the hypothalamus-pituitary-adrenal axis","volume":"15","author":"Thomas","year":"2019","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e13170","DOI":"10.1111\/nmo.13170","article-title":"Early-life adversity, epigenetics, and visceral hypersensitivity","volume":"29","author":"Liu","year":"2017","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1016\/j.lfs.2006.04.013","article-title":"Role of endogenous nitric oxide in mucosal defense of inflamed rat stomach following iodoacetamide treatment","volume":"79","author":"Nishio","year":"2006","journal-title":"Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Liu, L., Li, Q., Sapolsky, R., Liao, M., Mehta, K., Bhargava, A., and Pasricha, P.J. (2011). Transient gastric irritation in the neonatal rats leads to changes in hypothalamic CRF expression, depression- and anxiety-like behavior as adults. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019498"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1111\/apt.15191","article-title":"Review article: Treatment options for functional dyspepsia","volume":"49","author":"Masuy","year":"2019","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e13769","DOI":"10.1111\/nmo.13769","article-title":"Open-label pilot study: Non-invasive vagal nerve stimulation improves symptoms and gastric emptying in patients with idiopathic gastroparesis","volume":"32","author":"Adler","year":"2020","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/nature01321","article-title":"The inflammatory reflex","volume":"420","author":"Tracey","year":"2002","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1172\/JCI30555","article-title":"Physiology and immunology of the cholinergic antiinflammatory pathway","volume":"117","author":"Tracey","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/ca.1089","article-title":"The nerve supply of the human auricle","volume":"15","author":"Peuker","year":"2002","journal-title":"Clin. Anat."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"He, W., Jing, X.H., Zhu, B., Zhu, X.L., Li, L., Bai, W.Z., and Ben, H. (2013). The auriculo-vagal afferent pathway and its role in seizure suppression in rats. Bmc Neurosci., 14.","DOI":"10.1186\/1471-2202-14-85"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3135","DOI":"10.1007\/s11064-021-03396-w","article-title":"Xanthohumol Attenuates Lipopolysaccharide-Induced Depressive Like Behavior in Mice: Involvement of NF-kappaB\/Nrf2 Signaling Pathways","volume":"46","author":"Rahman","year":"2021","journal-title":"Neurochem. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"174396","DOI":"10.1016\/j.ejphar.2021.174396","article-title":"Antidepressant mechanism of catalpol: Involvement of the PI3K\/Akt\/Nrf2\/HO-1 signaling pathway in rat hippocampus","volume":"909","author":"Wang","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"136095","DOI":"10.1016\/j.neulet.2021.136095","article-title":"Synergistic effect between imipramine and citicoline upon induction of analgesic and antidepressant effects in mice","volume":"760","author":"Khakpai","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.jad.2016.02.031","article-title":"Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: A nonrandomized controlled pilot study","volume":"195","author":"Rong","year":"2016","journal-title":"J. Affect. Disord."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e13506","DOI":"10.1111\/eci.13506","article-title":"Functional dyspepsia in depression: A population-based cohort study","volume":"51","author":"Kao","year":"2021","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1136\/gutjnl-2011-300474","article-title":"The brain--gut pathway in functional gastrointestinal disorders is bidirectional: A 12-year prospective population-based study","volume":"61","author":"Koloski","year":"2012","journal-title":"Gut"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"680","DOI":"10.3389\/fnins.2020.00680","article-title":"Transcutaneous Auricular Vagus Nerve Stimulation at 20 Hz Improves Depression-Like Behaviors and Down-Regulates the Hyperactivity of HPA Axis in Chronic Unpredictable Mild Stress Model Rats","volume":"14","author":"Li","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1111\/joim.12611","article-title":"Vagus nerve stimulation: A new promising therapeutic tool in inflammatory bowel disease","volume":"282","author":"Bonaz","year":"2017","journal-title":"J. Intern. Med."},{"key":"ref_36","first-page":"8374614","article-title":"Gastrodiae Rhizoma Water Extract Ameliorates Hypothalamic-Pituitary-Adrenal Axis Hyperactivity and Inflammation Induced by Chronic Unpredictable Mild Stress in Rats","volume":"2020","author":"Wang","year":"2020","journal-title":"Biomed. Res. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1159\/000466698","article-title":"Differential Effects of Inflammatory and Psychosocial Stress on Mood, Hypothalamic-Pituitary-Adrenal Axis, and Inflammation in Remitted Depression","volume":"74","author":"Niemegeers","year":"2016","journal-title":"Neuropsychobiology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"33","DOI":"10.5056\/jnm14084","article-title":"Role of Corticotropin-releasing Factor in Gastrointestinal Permeability","volume":"21","author":"Pigrau","year":"2015","journal-title":"J. Neurogastroenterol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"51","DOI":"10.2174\/1874467210666170224095741","article-title":"Brain and Gut CRF Signaling: Biological Actions and Role in the Gastrointestinal Tract","volume":"11","author":"Tache","year":"2018","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e150052","DOI":"10.1172\/jci.insight.150052","article-title":"Ameliorating effects and mechanisms of transcutaneous auricular vagal nerve stimulation on abdominal pain and constipation","volume":"6","author":"Shi","year":"2021","journal-title":"JCI Insight"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1016\/j.cgh.2019.10.012","article-title":"Efficacy of Auricular Neurostimulation in Adolescents with Irritable Bowel Syndrome in a Randomized, Double-Blind Trial","volume":"18","author":"Krasaelap","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3575231","DOI":"10.1155\/2020\/3575231","article-title":"Sini-San Regulates the NO-cGMP-PKG Pathway in the Spinal Dorsal Horn in a Modified Rat Model of Functional Dyspepsia","volume":"2020","author":"Wu","year":"2020","journal-title":"Evid. Based Compl. Alt."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3727\/036012986816359247","article-title":"The effect of auricular electroacupuncture on the neuronal activity of the thalamic and hypothalamic neurons of the rat","volume":"11","author":"Ishibashi","year":"1986","journal-title":"Acupunct. Electrother. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.brs.2014.09.009","article-title":"Electrical stimulation of the vagus nerve dermatome in the external ear is protective in rat cerebral ischemia","volume":"8","author":"Ay","year":"2015","journal-title":"Brain Stimul."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1136\/acupmed-2014-010575","article-title":"Effects and mechanisms of auricular electroacupuncture on visceral pain induced by colorectal distension in conscious rats","volume":"32","author":"Li","year":"2014","journal-title":"Acupunct. Med."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/13\/2\/253\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:21:34Z","timestamp":1760120494000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/13\/2\/253"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,1]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["brainsci13020253"],"URL":"https:\/\/doi.org\/10.3390\/brainsci13020253","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,1]]}}}