Abstract
Objectives
The aims of this study were to investigate analgesic effects of vagus nerve stimulation
(VNS) on visceral hypersensitivity (VH) in a rodent model of functional dyspepsia
(FD) and to compare invasive VNS with noninvasive auricular VNS (aVNS).
Materials and Methods
Eighteen ten-day-old male rats were gavaged with 0.1% iodoacetamide (IA) or 2% sucrose
solution for six days. After eight weeks, IA-treated rats were implanted with electrodes
for VNS or aVNS (n = 6 per group). Different parameters, varying in frequency and stimulation duty cycle,
were tested to find the best parameter based on the improvement of VH assessed by
electromyogram (EMG) during gastric distension.
Results
Compared with sucrose-treated rats, visceral sensitivity was increased significantly
in IA-treated “FD” rats and ameliorated remarkably by VNS (at 40, 60, and 80 mm Hg;
p ≤ 0.02, respectively) and aVNS (at 60 and 80 mm Hg; p ≤ 0.05, respectively) with the parameter of 100 Hz and 20% duty cycle. There was
no significant difference in area under the curve of EMG responses between VNS and
aVNS (at 60 and 80 mm Hg, both p > 0.05). Spectral analysis of heart rate variability revealed a significant enhancement
in vagal efferent activity while applying VNS/aVNS compared with sham stimulation
(p < 0.01). In the presence of atropine, no significant differences were noted in EMG
after VNS/aVNS. Naloxone blocked the analgesic effects of VNS/aVNS.
Conclusions
VNS/aVNS with optimized parameter elicits ameliorative effects on VH, mediated by
autonomic and opioid mechanisms. aVNS is as effective as direct VNS and has great
potential for treating visceral pain in patients with FD.
Keywords
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References
- Rome IV-functional GI disorders: disorders of gut-brain interaction.Gastroenterology. 2016; 150: 1257-1261https://doi.org/10.1053/j.gastro.2016.03.035
- Functional dyspepsia.Lancet. 2020; 396: 1689-1702https://doi.org/10.1016/S0140-6736(20)30469-4
- Gastroduodenal disorders.Gastroenterology. May 2016; 150: 1380-1392https://doi.org/10.1053/j.gastro.2016.02.011
- Functional dyspepsia impairs quality of life in the adult population.Aliment Pharmacol Ther. 2011; 33: 1215-1224https://doi.org/10.1111/j.1365-2036.2011.04640.x
- Functional dyspepsia: the economic impact to patients.Aliment Pharmacol Ther. 2013; 38: 170-177https://doi.org/10.1111/apt.12355
- Current management strategies and emerging treatments for functional dyspepsia.Nat Rev Gastroenterol Hepatol. 2013; 10: 187-194https://doi.org/10.1038/nrgastro.2013.11
- Management of functional dyspepsia: state of the art and emerging therapies.Ther Adv Chronic Dis. 2018; 9: 23-32https://doi.org/10.1177/2040622317725479
- Effects and mechanisms of acupuncture and electroacupuncture for functional dyspepsia: a systematic review.World J Gastroenterol. 2020; 26: 2440-2457https://doi.org/10.3748/wjg.v26.i19.2440
- You may need a nerve to treat pain: the neurobiological rationale for vagal nerve activation in pain management.Clin J Pain. 2014; 30: 1099-1105https://doi.org/10.1097/AJP.0000000000000071
- A review of vagus nerve stimulation as a therapeutic intervention.J Inflamm Res. 2018; 11: 203-213https://doi.org/10.2147/Jir.S163248
- Autonomic arousal and experimentally induced pain: a critical review of the literature.Pain Res Manag. 2014; 19: 159-167https://doi.org/10.1155/2014/536859
- Vagal modulation of nociception is mediated by adrenomedullary epinephrine in the rat.Eur J Neurosci. 2003; 17: 909-915https://doi.org/10.1046/j.1460-9568.2003.02503.x
- Subdiaphragmatic vagal afferent innervation in activation of an opioidergic antinociceptive system in response to colorectal distension in rats.Neurogastroenterol Motil. 2002; 14: 403-408https://doi.org/10.1046/j.1365-2982.2002.00345.x
- Vagus nerve stimulation attenuates heat- and formalin-induced pain in rats.Neurosci Lett. 2003; 351: 79-82https://doi.org/10.1016/S0304-3940(03)00908-X
- The effect of transcutaneous vagus nerve stimulation on pain perception - an experimental study.Brain Stimul. 2013; 6: 202-209https://doi.org/10.1016/j.brs.2012.04.006
- A rat model of chronic gastric sensorimotor dysfunction resulting from transient neonatal gastric irritation.Gastroenterology. 2008; 134: 2070-2079https://doi.org/10.1053/j.gastro.2008.02.093
- Transient gastric irritation in the neonatal rats leads to changes in hypothalamic CRF expression, depression- and anxiety-like behavior as adults.PLoS One. 2011; 6e19498https://doi.org/10.1371/journal.pone.0019498
- The analgesic effects of the GABAB receptor agonist, Baclofen, in a rodent model of functional dyspepsia.Neurogastroenterol Motil. 2011; 23 (e160–e161): 356-361https://doi.org/10.1111/j.1365-2982.2010.01649.x
- Inhibitory effects and mechanisms of electroacupuncture via chronically implanted electrodes on stress-induced gastric hypersensitivity in rats with neonatal treatment of iodoacetamide.Neuromodulation. 2017; 20: 767-773https://doi.org/10.1111/ner.12602
- Effects and mechanisms of auricular electroacupuncture on gastric hypersensitivity in a rodent model of functional dyspepsia.PLoS One. 2017; 12e0174568https://doi.org/10.1371/journal.pone.0174568
- Vagal nerve stimulation for glycemic control in a rodent model of Type 2 diabetes.Obes Surg. 2019; 29: 2869-2877https://doi.org/10.1007/s11695-019-03901-9
- Auricular vagal nerve stimulation improves constipation by enhancing colon motility via the central-vagal efferent pathway in opioid-induced constipated rats.Neuromodulation. 2021; 24: 1258-1268https://doi.org/10.1111/ner.13406
- A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development.Gastroenterology. 2000; 119: 1276-1285https://doi.org/10.1053/gast.2000.19576
- A model for evaluation of gastric sensitivity in awake rats.Neurogastroenterol Motil. 1998; 10: 157-163https://doi.org/10.1046/j.1365-2982.1998.00091.x
- Models of gastric hyperalgesia in the rat.Am J Physiol Gastrointest Liver Physiol. 2002; 283: G666-G676https://doi.org/10.1152/ajpgi.00001.2002
- Vagal afferent is involved in short-pulse gastric electrical stimulation in rats.Dig Dis Sci. 2004; 49: 729-737https://doi.org/10.1023/b:ddas.0000030081.91006.86
- Ameliorating effects and mechanisms of electroacupuncture on gastric dysrhythmia, delayed emptying, and impaired accommodation in diabetic rats.Am J Physiol Gastrointest Liver Physiol. 2010; 298: G563-G570https://doi.org/10.1152/ajpgi.00252.2009
- Electroacupuncture at ST36 relieves visceral hypersensitivity via the NGF/TrkA/TRPV1 peripheral afferent pathway in a rodent model of post-inflammation rectal hypersensitivity.J Inflam Res. 2021; 14 (Published correction appears in J Inflamm Res. 2021;14:393): 325-339https://doi.org/10.2147/JIR.S285146
- Optimum numerical integration methods for estimation of area-under-the-curve (AUC) and area-under-the-moment-curve (AUMC).J Pharmacokinet Biopharm. 1992; 20: 211-226https://doi.org/10.1007/BF01062525
- 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.Lancet Gastroenterol Hepatol. 2018; 3: 252-262https://doi.org/10.1016/S2468-1253(18)30003-7
- Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia.Gastroenterology. 2001; 121: 526-535https://doi.org/10.1053/gast.2001.27180
- Dyspeptic patients with visceral hypersensitivity: sensitisation of pain specific or multimodal pathways?.Gut. 2005; 54: 914-919https://doi.org/10.1136/gut.2004.052605
- In functional dyspepsia, hypersensitivity to postprandial distention correlates with meal-related symptom severity.Gastroenterology. 2013; 145: 566-573https://doi.org/10.1053/j.gastro.2013.05.018
- Effects and mechanisms of gastric electrical stimulation on visceral pain in a rodent model of gastric hyperalgesia secondary to chemically induced mucosal ulceration.Neurogastroenterol Motil. 2014; 26: 176-186https://doi.org/10.1111/nmo.12248
- Neuro-immune modulation effects of sacral nerve stimulation for visceral hypersensitivity in rats.Front Neurosci. 2021; 15645393https://doi.org/10.3389/fnins.2021.645393
- Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects.Neurosci Biobehav Rev. 2005; 29: 493-500https://doi.org/10.1016/j.neubiorev.2005.01.004
- Mobilization of specific neuropeptides by peripheral stimulation of identified frequencies.Physiology. 1992; 7: 176-180
- Increased sympathetic activity in chronic pancreatitis patients is associated with hyperalgesia.J Pain Palliat Care Pharmacother. 2010; 24: 362-366https://doi.org/10.3109/15360288.2010.519762
- Transcutaneous auricular vagal nerve stimulation improves functional dyspepsia by enhancing vagal efferent activity.Am J Physiol Gastrointest Liver Physiol. 2021; 320: G700-G711https://doi.org/10.1152/ajpgi.00426.2020
- Antinociception and cardiovascular responses produced by intravenous morphine: the role of vagal afferents.Brain Res. 1991; 543: 256-270https://doi.org/10.1016/0006-8993(91)90036-u
- Therapeutic mechanisms of vagus nerve stimulation.Neurology. 2002; 59 (S3–S14)https://doi.org/10.1212/wnl.59.6_suppl_4.s3
- Ligand-directed signalling within the opioid receptor family.Br J Pharmacol. 2012; 167: 960-969https://doi.org/10.1111/j.1476-5381.2012.02075.x
- Characterization of opioidergic mechanisms related to the anti-migraine effect of vagus nerve stimulation.Neuropharmacology. 2021; 195108375https://doi.org/10.1016/j.neuropharm.2020.108375
- Acute autonomic engagement assessed by heart rate dynamics during vagus nerve stimulation in patients with heart failure in the ANTHEM-HF trial.J Cardiovasc Electrophysiol. 2016; 27: 1072-1077https://doi.org/10.1111/jce.13017
- Differential hemodynamic and respiratory responses to right and left cervical vagal nerve stimulation in rats.Physiol Rep. 2017; 5e13244
- A neural circuit for gut-induced reward.Cell. 2018; 175: 887-888https://doi.org/10.1016/j.cell.2018.10.018
- Self-administration of right vagus nerve stimulation activates midbrain dopaminergic nuclei.Front Neurosci. 2021; 15782786https://doi.org/10.3389/fnins.2021.782786
- Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease.J Intern Med. 2017; 282: 46-63https://doi.org/10.1111/joim.12611
- Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia.Gut. 2014; 63: 262-271https://doi.org/10.1136/gutjnl-2012-303857
- Considerations for safety with chronically implanted nerve electrodes.Epilepsia. 1990; 31: S27-S32https://doi.org/10.1111/j.1528-1157.1990.tb05845.x
- A review of parameter settings for invasive and non-invasive vagus nerve stimulation (VNS) applied in neurological and psychiatric disorders.Front Neurosci. 2021; 15709436https://doi.org/10.3389/fnins.2021.709436
Comment
Article info
Publication history
Published online: May 15, 2023
Accepted:
April 10,
2023
Received in revised form:
March 20,
2023
Received:
January 4,
2023
Publication stage
In Press Corrected ProofFootnotes
Source(s) of financial support: The authors reported no funding for this work.
Conflict of Interest: The authors reported no conflict of interest.
Identification
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© 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.
