Optimization of electrical stimulation modalities for treating visceral pain in a rodent model of irritable bowel syndrome

doi:10.21203/rs.3.rs-4764737/v1

Download PDF

Research Article

Optimization of electrical stimulation modalities for treating visceral pain in a rodent model of irritable bowel syndrome

https://doi.org/10.21203/rs.3.rs-4764737/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 11 Nov, 2024

Read the published version in Bioelectronic Medicine →

You are reading this latest preprint version

The purpose of this study was to investigate the effects of different electrical stimulation methods (bilateral electroacupuncture (BEA), unilateral EA (UEA), transcutaneous electrical acustimulation (TEA, stimulation via surface electrodes placed at acupoints), and sacral nerve stimulation (SNS)) on visceral pain in a rodent model of irritable bowel syndrome (IBS). Ten-day-old male and female pups were treated with 0.2 ml of 0.5% acetic acid (AA) solution. Visceral sensitivity was assessed using an electromyogram (EMG) in response to graded colorectal distension. In the first experiment, bilateral EA at ST36 acupoint was performed with different parameters in male rats to determine the best stimulation parameters. In the second experiment, male rats were randomly assigned into the Sham, BEA, UEA, TEA, and SNS groups to determine the best stimulation method. Lastly, the AA-treated female rats were randomly assigned into the BEA and sham groups to investigate a potential treatment difference between the sexes. Results: 1) The parameter set of 100Hz was found to be most effective in reducing visceral pain. 2) Both acute UEA and TEA effectively relieved visceral pain, whereas acute SNS did not exhibit such an effect. 3) Acute BEA improved visceral pain in both male and female rats. Conclusions: These findings suggest that transcutaneous ST36 stimulation is as effective as direct ST36 stimulation and unilateral ST36 stimulation is comparable to bilateral stimulation. Development of a novel therapy using unilateral transcutaneous ST36 stimulation is warranted.

Electroacupuncture

transcutaneous electrical acustimulation

visceral pain

irritable bowel syndrome

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders, which is characterized by the occurrence of chronic and recurrent abdominal pain, bloating, distention, and changes in bowel habits. IBS affects between 5–10% of the global population [1; 2], and women are at higher risk for IBS than men. The etiology of pain in IBS is not well understood. However, clinical and animal studies suggest that sensitization of visceral afferents, spinal dorsal horns, and dysfunction of the descending modulatory systems may have an important role. The brain receives nociceptive pain signals from the visceral organs, including the GI tract, and inputs from these overly sensitive nerves are responsible for pain perception. This bidirectional interaction between the brain and gut is essential for maintaining GI homeostasis and higher cognitive functions [3; 4; 5]. Visceral hypersensitivity, characterized by hypersensitivity to a stimulus, is another crucial feature of IBS and is thought to underlie abdominal pain in patients with IBS. Several mechanisms may contribute to this feature, including mast cell activation, increased mucosal permeability, sensitization of visceral afferents, and dietary habits. Psychiatric comorbidities such as depression and anxiety are prevalent in IBS patients and correlate with enhanced visceral pain perception, which may play a role in the pathogenesis of IBS [3; 4; 5].

The pathogenesis of IBS is complicated and multifactorial; therefore, treating pain in IBS is challenging. Standard treatment methods include anticholinergic agents, antidepressants, such as tricyclic antidepressants (TCAs), serotonin reuptake inhibitors (SSRIs), and monoamine uptake inhibitors. Anticholinergic agents such as hyoscyamine and dicyclomine reduce abdominal pain and discomfort by reducing spasms or contractions in the intestine. Antidepressants decrease pain perception by regulating nerve signaling and can potentially increase or decrease GI function. These drugs have therapeutic effects on mood, sleep, and associated psychological disturbances [6; 7; 8; 9]. SSRIs improve overall well-being, reduce anxiety associated with IBS, and enhance the analgesic properties of TCAs, suggesting that SSRIs may decrease pain in IBS patients. Serotonin receptors (e.g., Tegaserod and Alosetron) increase gut movement and intestinal secretions by working on the nerves and GI smooth muscles. These agents improve pain and bloating in IBS patients. Although these drugs improve pain and overall symptoms in IBS, unsatisfactory side effects, such as headache, dizziness, dry mouth, insomnia, cardiovascular disorders, and ischemic colitis, exist. Due to the disease's heterogeneous nature, treatment options are minimal and often controversial; therefore, alternative treatment methods, such as electrical neuromodulation, could be beneficial.

Neuromodulation is an emerging field in medical sciences that modulates or changes the functioning of the central, peripheral, or autonomic nervous system. It acts directly or indirectly on nerves and alternates or modulates nerve activity using electrical, chemical, and mechanical interventions [10]. Neuromodulation can be invasive and noninvasive. Invasive neuromodulation requires a surgical procedure to implant stimulating electrodes. Sacral nerve stimulation (SNS) is one of the most common invasive neuromodulation methods. It is FDA-approved for treating overactive bladder and fecal incontinence; its potential for treating pain in IBS has also been explored [11]. Noninvasive neuromodulation typically involves transcutaneous electrical stimulation that can penetrate the skin to stimulate nerves. Some of these methods include electroconvulsive therapy (ECT), transcranial electrical stimulation (TES), transcranial direct current stimulation (tDCS), electroacupuncture (EA), transcutaneous auricular vagal nerve stimulation (taVNS), transcutaneous electrical acustimulation (TEA) or transcutaneous electrical acupoint stimulation (TEAS), and transcutaneous tibial nerve stimulation (tTNS) [12]. Preclinical and clinical studies have suggested that EA and TEA could be used for managing pain in IBS. EA at the ST36 acupoint with a frequency of 100 Hz effectively enhanced rectal compliance and alleviated visceral hypersensitivity in rats with intestinal inflammation induced by 5% dextran sulfate sodium (DSS) [13]. TEA improved bowel movements, alleviated abdominal pain, and improved colon transit and rectal sensation through autonomic mechanisms in constipation-dominant IBS patients [14].

Preliminary clinical studies from our group with TEA at bilateral acupuncture points, ST36, have shown an analgesic effect in patients with IBS [14; 15]. However, bilateral stimulation limits the mobility of patients. Therefore, it is essential to determine whether unilateral stimulation on one leg is equally effective as this would allow patients to resume daily activity during the treatment. In addition, it is unknown whether the noninvasive ST36 simulation method via surface electrodes is as potent as ST36 stimulation via inserted needles or direct electrical stimulation of the sacral nerve that innervates the colon (SNS), which has been clinically used for treating various pelvic floor disorders [11; 16].

Accordingly, this study aimed to investigate the effects of different stimulation modalities on visceral hypersensitivity in a rodent model of IBS by comparing different stimulation parameters, bilateral vs. unilateral stimulation, EA via needles vs. TEA via surface electrodes, and EA vs. SNS. Furthermore, we investigated potential treatment differences between males and females.

Animals

Forty-six Sprague-Dawley rat pups (28 males and 18 females) were purchased from Charles River Laboratories in Kingston, NY, USA, at the age of nine days. On postnatal day 10 (P10), the rat pups received a manual intracolonic injection of 0.2 mL of 0.5% acetic acid (AA) into the distal colon, specifically 2 cm from the anus [17]. Food and water were provided ad libitum, and all animals were maintained at room temperature under a 12:12-hour light/dark cycle.

Surgical procedures

Electrode implantation surgery was performed during 8–9 weeks of age for four different purposes: Bilateral electroacupuncture (BEA), Unilateral electroacupuncture (UEA), Sacral nerve stimulation (SNS), and recording abdominal electromyography (EMG). Rats were anesthetized with 2% isoflurane (Piramal Critical Care Inc., Bethlehem, PA, USA) with a 2 liter/min oxygen flow. The body temperature was maintained at 37°C during the surgery, and an ophthalmic ointment was applied to the eyes to prevent dryness.

EMG electrode implantation: A pair of stainless-steel wires (Cardiac pacing wires, A&E Medical, Farmingdale, NJ, USA) was inserted into the abdominal muscle to record the EMG response to colorectal distention (CRD) [18; 19].

ST36 electrode implantation: A pair of the same wires was inserted bilaterally into acupoints ST36, located 5 mm below the head of the fibula, under the knee joint, and 2 mm lateral to the anterior tubercle of the tibia in rats. The electrode wires were inserted bilaterally at a depth of 5 mm into the muscles at ST36 and secured with sutures [20]. For unilateral ST36 stimulation, another electrode was placed 5 mm below the ST36 acupoint on either the left or right leg.

SNS electrode implantation: A dorsal midline incision was made to expose the right sacral nerve. One pair of electrodes (Streamline 6494F, Medtronic, Minneapolis, MN, USA) were placed around the right sacral nerve (S1) behind the sacral foramen and fixed by a surgical knot (oval cathode 2–3 mm in length in each electrode). To isolate the exposed wires from the adjacent tissues, we used Kwik-Sil (World Precision Instruments, Sarasota, FL, USA) on the wires [18; 21].

All electrode connecting wires were tunneled subcutaneously and brought out at the back of the neck. Post-surgery, Carprofen (5 mg/kg) and Enrofloxacin (5 mg/kg) were administered for two days to control infection and postoperative pain, respectively. The rats were allowed to recover for seven days before the experiment. All male and female rats received electrode implantation in the abdomen. Among the 28 male rats, 11 received electrode implantation in the S1 and ST36 locations (cohort-1, Fig. 1A), 9 in the ST36 location (cohort-2, Fig. 1B), and 8 in the S1 location (cohort-3, Fig. 1C), while female rats received electrode implantation in the ST36 location (Female cohort, Fig. 1D).

Experiment design

In this study, we used forty-six (n = 46) neonatally AA-treated rats. In the first cohort, rats were randomized for Sham (stimulation output set at 0mA), BEA, UEA, BEA-25Hz, and SNS stimulation (Fig. 1A). In the second cohort, rats underwent Sham and BEA in randomized order (Fig. 1B). Three to four days after the last stimulation, rats were subjected to TEA (Fig. 1B). The third cohort of rats received Sham and SNS stimulation in a randomized order (Fig. 1C). Among the 18 male rats, 13 received Sham or BEA in randomized order (Fig. 1D).

Thirty minutes after inserting a balloon under isoflurane anesthesia (see Visceromotor reflex (VMR) response to CRD section below for details), electrical stimulation was delivered via the stimulating wires using a digital stimulator (World Precision Instrument, Sarasota, FL, USA). After 15 minutes of stimulation (BEA, UEA, or TEA), EMG responses were measured with graded colorectal distension (CRD). The stimulation was continuous except during the EMG measurement (Fig. 1E). However, the SNS group received 30 minutes of stimulation and no stimulation during the EMG measurement (Fig. 1F).

BEA: BEA was performed using two different sets of parameters: Set 1: 0.1s on, 0.4s off, 100Hz, and 0.5ms pulse width; this parameter was previously used for relieving visceral pain [13; 22] and Set 2: 2s on, 3s off, 25Hz, 0.5ms; this parameter was shown to accelerate gastric motility in previous studies [23; 24]. In the case of both stimulation parameters, the amplitude was set at the motor threshold (MT) to evoke muscle contractions surrounding ST36 acupoints (0.4 ~ 3.0 mA).

UEA: UEA was performed using stimulation parameter set 1. Stimulation was performed using one electrode inserted at ST36 and another electrode inserted at 5 mm below ST36. The stimulation amplitude was determined to be the minimum current required to induce muscle contraction surrounding ST36 acupoints.

SNS: SNS was performed using parameter set 1 and the amplitude was set at 80% of the MT (0.4 ~ 2.0 mA). The MT is defined as the stimulation amplitude required to elicit the first observable motor response of the rodent tail.

TEA: TEA was achieved bilaterally using surface patch electrodes, and a watch-size digital stimulator (SNM-FDC01, Ningbo MedKinetic, Ningbo, China) was used to deliver electrical stimulation. Before the attachment of electrodes, the hair and area of ST36 were shaved and cleaned using alcohol. Then, a conducting gel was applied to reduce impedance, and one electrode was placed over each ST36 point and fixed with tape. Stimulation parameter set 1 was used and the amplitude was set at a level that induced contractions of muscle surrounding ST36 (0.3-5.0 mA)

Visceromotor reflex (VMR) response to CRD

We employed a previously established method [17; 25] to assess the visceromotor reflex in response to CRD. Under mild sedation with 1–2% isoflurane, a flexible balloon (5 cm) constructed from a surgical glove finger attached to a Tygon tube was inserted into the descending colon and rectum 8cm from the anal verge and held in place by taping the tube to the tail. The rat was placed in a transparent restrainer and allowed to adapt for 30 min before the test. CRD was performed by rapidly inflating the balloon to predefined constant pressures of 10, 20, 40, 60, and 80 mmHg for a 20-s period, each followed by a 4-minute rest at a pressure of 0 (Fig. 1E, F). After 4 minutes of rest, the whole process was repeated one more time (you did 4 CRD procedures, 2 at baseline and 2 after stimulation? No, only one sham stimulation, which is used to compare with each treatment). The EMG response was recorded continuously during the experiment using a Biopac system EMG 100C (Biopac Systems Inc., Goleta, CA, USA). The EMG signal was amplified from 1Hz to 5000 Hz and digitized using the Acknowledge (Biopac Systems, Inc.). The area under the curve (AUC) of the EMG signal during each 20s distention period was calculated using an in-house written computer program [18] (Cite a ref. I did not find the original paper; however, the cited article used the same method and did not cite references). The net EMG value for each distension, representing the strength of visceromotor reflexes, was calculated by subtracting the baseline value derived from the AUC for the 20s pre-distention period.

Data exclusion: During our study, we encountered specific instances where data had to be excluded to uphold the integrity and reliability of our analysis. These exclusions were carried out in accordance with standard scientific practices and guidelines. One male rat was removed from the dataset due to an outlier value observed during the Sham EA stimulation, and subsequently, the rat died. Five female rats were not subjected to acute BEA stimulation. As a result, they were not included in the subsequent analysis.

Statistical analysis

All data are presented as mean ± SEM. Statistical analyses were performed using Prism version 10 software (GraphPad). Multiple group comparisons were assessed using one-way, two-way, or repeated-measures ANOVA, followed by the appropriate post hoc test when significant main effects or interactions were detected. The null hypothesis was rejected at the p < 0.05 level.

1. Effects of Different Electrical Stimulation Methods on Visceral Pain in AA-treated Male Rats

a) Acute BEA Improved Visceral Pain

In this experiment, we tested the effects of acute BEA on EMG in response to CRD using two different stimulation parameters. Acute BEA with pain parameter (set 1; BEA-100Hz), but not motility parameter (set 2; BEA-25Hz), significantly reduced EMG in response to CRD in AA-treated male rats compared to the Sham stimulation (Fig. 2). BEA dramatically reduced EMG at 20, 40, 60, and 80 mmHg [Sham vs. BEA (20 mmHg, 596.28 ± 102.1 vs. 200.4 ± 46.39, p = 0.027; 40 mmHg, 1115 ± 108.89 vs. 520.8 ± 74.97, p = 0.0002; 60 mmHg, 1371 ± 128.38 vs. 760.9 ± 87.69, p < 0.0001, 80mmHg, 1534 ± 148.09 vs. 912.6 ± 94.39, p < 0.0001), Bonferroni's multiple comparisons tests, Fig. 2A], but not at 10 mmHg (Sham vs BEA, 254.3 ± 76.80 vs 43.96 ± 9.43, p = 0.619, Bonferroni's multiple comparisons tests, Fig. 2A) compared to the Sham group. More importantly, BEA with motility parameter (BEA-25Hz) had no effects on visceral pain in AA-treated male rats (Two-way repeated measures ANOVA, p = 0.326, Fig. 2B).

b) Acute SNS did not Improve Visceral Pain

Next, we investigated whether direct sacral nerve stimulation (SNS) ameliorates visceral pain in AA-treated male rats. The effect of SNS with the same pain parameters was less potent, and there were no significant differences in EMG in response to CRD between the Sham and the SNS group (Two-way repeated measures ANOVA, p = 0.578, Fig. 2C).

c) TEA via Surface Electrodes Improved Visceral Pain

Previous studies in humans suggest that TEA at the acupoints of ST36 improved visceral pain in patients with IBS [14; 15]. Moreover, TEA has several advantages, including its non-invasiveness and home-based therapy. Therefore, we tested whether TEA using surface electrodes had a similar ameliorating effect on visceral pain in AA-treated male rats. We found that acute TEA improved visceral pain in AA-treated male rats (Fig. 2D). TEA decreased EMG responses, in comparison with the Sham group, during CRD at 40, 60, and 80 mmHg [Sham vs. TEA (40 mmHg, 1189 ± 94.16 vs. 550.0%±86.84, p = 0.001; 60mmHg, 1475 ± 121.82 vs. 959.4 ± 149.73, p = 0.012; 80 mmHg, 1729 ± 171.63 vs. 1124 ± 118.40, p = 0.002), Bonferroni's multiple comparisons tests, Fig. 2D], but not at 10 and 20 mmHg [Sham vs TEA (10 mmHg, 133.1 ± 40.42 vs 116.5 ± 37.95, p > 0.99; 20 mmHg, 457.1 ± 118.36 vs 259.8 ± 81.92, p > 0.99), Bonferroni's multiple comparisons tests].

d) Acute UEA Improved Visceral Pain

Clinically, unilateral stimulation is more straightforward to implement as it allows the subject to resume regular activities. Accordingly, we tested whether UEA had a similar beneficial effect on visceral pain as BEA. In AA-treated male rats, we observed that UEA showed a similar beneficial effect on visceral pain as BEA (Fig. 3). UEA decreased EMG in response to CRD at 40, 60, and 80 mmHg [Sham vs. UEA (40 mmHg, 1101 ± 104.13 vs. 671.9 ± 146.07, p = 0.022; 60 mmHg, 1345 ± 124.28 vs. 804.3 ± 141.98, p = 0.002, 1506 ± 143.0 vs. 817.8 ± 139.14, p < 0.0001), Tukey's multiple comparisons tests, Fig. 3], but not at 10 and 20 mmHg [Sham vs UEA (10 mmHg, 258.0 ± 72.85 vs 107.3 ± 61.71, p = 0.62; 20 mmHg, 585.4 ± 97.30 vs 394.2 ± 98.13, p = 0.46), Tukey's multiple comparisons tests, Fig. 3]. No difference was noted between UEA and BEA.

2. Acute BEA Improves Visceral Pain in Female Rats

IBS is more commonly diagnosed in women than in men. Studies have shown that women are about two to three times [26] more likely to be diagnosed with IBS. Therefore, we tested whether acute BEA was effective in AA-treated female rats. Interestingly, BEA in female rats demonstrated similar ameliorating effects in reducing visceral pain. BEA-100Hz in female rats improved EMG in response to CRD at 60 and 80 mmHg [Sham vs BEA (60 mmHg, 1311 ± 150.92 vs 810.2 ± 87.44, p = 0.007; 80 mmHg, 1547 ± 214.39 vs 975.7 ± 92.98, p = 0.001), Bonferroni's multiple comparisons tests, Fig. 4A]. We did not observe any significant differences at 10, 20, and 40 mmHg [Sham vs BEA (10 mmHg, 72.5 ± 35.10 vs 7.43 ± 19.93, p > 0.999; 20 mmHg, 319.6 ± 79.32 vs 166.4 ± 36.59, p > 0.999; 40 mmHg, 899.3 ± 98.32 vs 533.3 ± 74.39, p = 0.095), Bonferroni's multiple comparisons tests, Fig. 5A]. More importantly, Sham-EA and BEA had similar effects on EMG responses to CRD in AA-treated male and female rats [Sham-EA (male vs female, Two-way repeated measures ANOVA, p = 0.487, Fig. 4B] and [BEA (male vs female, Two-way repeated measures ANOVA, p = 0.815, Fig. 4C].

Our results demonstrate that acute BEA at ST36 acupoints improved visceral pain in AA-treated IBS rats. This finding is consistent with our previous study, where EA at ST36 acupoint with a similar stimulation protocol significantly reduced visceral hypersensitivity in rats [13]. Moreover, acute applications of UEA and TEA at ST36 demonstrated effectiveness in alleviating visceral pain in IBS rats. These results suggest that TEA is as effective as direct ST36 stimulation (BEA). However, acute SNS stimulation did not reduce visceral pain in AA-treated rats. Previous studies demonstrated that acute SNS at 14 Hz, pulse width of 330 ms, and stimulation amplitude of 40% MT normalized acute restraint stress-induced visceral hypersensitivity in rats [18]. Other research demonstrated that SNS with the 5 Hz, 500 µs, 10 seconds on, 90 seconds off parameters increased vagal activity and decreased sympathetic activity in 2, 4, 6-Trinitrobenzenesulfonic acid (TNBS) induced rats [21; 27]. The variation in results could be attributed to differences in the animal model and stimulation parameters used in these studies. Furthermore, our results demonstrate that acute BEA at ST36 improved visceral pain in female rats, suggesting similar efficacy between the sexes.

The animal model we used in this study to induce IBS is well-established. These animals develop visceral hypersensitivity in adulthood, and the visceral pain response can be measured with EMG in response to CRD [28; 29]. CRD is a reproducible and reliable visceral stimulus, which is helpful in assessing visceral pain [30]. The abdominal EMG is a well-established method for assessing visceral pain in animal models that measure the electromyogram signal (reflecting abdominal muscle contractions) generated during the CRD. Acupoint ST36 stimulation is most commonly used in clinical settings to treat GI disorders, including IBS [31]. Furthermore, acupoint ST36 is a critical site that modulates sympathetic and parasympathetic nervous systems since it is in the vicinity of peroneal, sciatic, and tibial nerves. Stimulation at ST36 impacts distal gut functions through anatomical proximity and influences upper gut functions through a functional connection with the central and vagal nerve systems [32; 33; 34]. Accordingly, we chose to use AA-treated IBS model rats, EMG as a surrogate for pain measurement, and ST36 as the focus of our research study.

Most interestingly, the findings of this comparative methodological study demonstrated similar ameliorating effects between unilateral and bilateral stimulation, and between direct ST36 stimulation and transcutaneous ST36 stimulation. These findings suggest a novel therapeutic approach for pain in IBS: unilateral transcutaneous ST36 stimulation. This unilateral TEA method will have several advantages: 1) it is completely noninvasive; 2) it can be self-administered at home since it does not use needles: 3) the unilateral stimulation (preferably use of a wireless wearable stimulator) does not interfere with daily activity of the user.

IBS is more predominant in women than in men, with a female-to-male ratio of 2–2.5:1 [26]. However, its pathophysiologic mechanisms are still unclear. While both men and women with IBS experience similar symptoms, including abdominal pain or discomfort, diarrhea, and constipation, women experience more abdominal pain and constipation-related symptoms. Sex hormones are thought to play a critical role that most influences the clinical manifestation and physiologic responses in men and women with IBS. Some research suggests that women may have increased sensitivity to visceral pain compared to men. This heightened sensitivity could contribute to differences in the perception and experience of IBS symptoms between genders [26; 35]. While IBS can significantly impact the quality of life for both men and women, studies have found that women with IBS may experience more severe symptoms and more significant impairment in quality of life compared to men. Understanding these similarities and differences in the medical care environment and applying them to IBS patients can help healthcare providers tailor treatment approaches for individuals with IBS.

Alteration in the inputs from the gut, known as afferent sensitization, is thought to play a crucial role in pain sensitization in patients with IBS [2; 36]. Under pathophysiological conditions, primary visceral afferent neurons, aka vagal afferent, convey pain signals from the viscera to the NTS [37]. On the other hand, spinal visceral afferent neurons from the intestinal tract are located in different spinal segments, and this viscerosomatic cross-organ sensitization may be involved in a central mechanism of nociceptive signaling. For example, increased expression of transient receptor potential vanilloid type-1 (TRPV1) contributes to visceral hypersensitivity and pain [38]. Thus, afferent sensitization is an important factor contributing to pain in IBS. EA at ST36 significantly decreased chronic visceral hypersensitivity and colon 5-HT3 receptor levels in AA-treated rats [39]. Moreover, EA decreased rectal sensitivity by decreasing TRPV1 in both colon and dorsal root ganglions [13]. Pre-EA at acupoint EX-B2 significantly reduced intracolonic formalin-induced visceral pain by decreasing p38 phosphorylation and c-Fos expression in the spinal cord and colon [40]. Colonic biopsies from IBS patients had elevated mucosal N-methyl-D-aspartate receptor (NMDAR) levels that were positively correlated with the severity and rate of recurrence of abdominal symptoms [41]. Clinical and animal studies demonstrated that administering NMDAR antagonist dextromethorphan in IBS patients and MK801 in mice blocked somatic and visceral hypersensitivity [41; 42]. Moreover, the injection of D-2-amino-5-phosphonopentanoate (AP5) into the rostral ventromedial medulla (RVM) inhibited visceral pain [43], and locus coeruleus-RVM circuit was found to be essential for the comorbidity of colorectal visceral pain [44]. EA at ST36 and ST37 improved visceral hyperalgesia, decreased c-Fos, and NMDAR expression in the RVM in IBS model rats [45], suggesting an analgesic effect of EA, which may mediated by inhibiting NMDAR activation in the RVM. These studies have suggested that EA desensitizes visceral and sensory afferents and improves visceral pain in IBS.

Chronic, low-grade inflammation is thought to play a critical role in the pathophysiology of IBS [46; 47]. Increased levels of inflammatory cytokines, including interleukin (IL)-6, IL-1β, IL-8, and tumor necrosis factor (TNF)-α, have been reported in the blood and serum of IBS model animals and IBS patients [48; 49; 50]. A clinical study demonstrated that increased levels of serotonin (5-HT) in IBS patients contributed to abdominal pain [51]. Thus, low-grade inflammation may contribute to pain in IBS patients. EA reduced pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, and suppressed myeloperoxidase activity in the colon via the autonomic mechanism [20]. Another research showed that EA suppressed the expression of inflammatory cytokines, such as IL-8, IFN-γ, and TNF-α and in water avoidance stress (WAS) induced IBS mice and alleviated pain by suppressing the expression of inflammatory cytokines, such as IL-8, IFN-γ, and TNF-α [52]. Results from these studies suggest that EA may improve pain in IBS by reducing inflammation.

The role of the cholinergic anti-inflammatory pathway in reducing inflammation in GI disorders is well-documented [53; 54; 55]. This pathway functions through vagal efferent fibers that link to enteric neurons and release acetylcholine [56; 57]. Disruption of this pathway can synthesize pro-inflammatory cytokines, including TNF- α and IL-1, which may lead to intestinal mucosal inflammation, thus contributing to visceral pain. Upon parasympathetic activation, enteric neurons release acetylcholine, which interacts with α7 nicotinic acetylcholine receptors (α7nAChRs) on macrophages, inhibiting pro-inflammatory cytokine production [58]. Moreover, by activating parasympathetic outflow, the cholinergic anti-inflammatory pathway inhibits macrophage activation and regulates inflammation [53]. EA at ST36 restored the impaired colonic contraction and transit induced by rectal distension by enhancing vagal activity and mediated via the cholinergic pathway [59].

The gastrointestinal epithelium acts as a barrier, preventing the penetration of harmful substances in the lumen from other tissues via the intestinal mucosa. Human and animal studies have reported increased intestinal permeability in GI disorders [60; 61]. Previous studies reported that alteration in epithelial tight junctions (TJ) proteins, such as Zonula Occludens (ZO-1), Claudins, and Occludin, led to epithelial barrier dysfunction and contributed to the pathogenesis of IBS and pain [61; 62; 63]. EA increased ZO-1 and enhanced the repair of the intestinal mucosal barrier by decreasing corticotropin-releasing factor-receptor 1 expression in the gastrointestinal mucosa [64], as well as EA improved intestinal permeability by increasing the expression of TJ proteins in IBS mice and rats [52; 65]. Thus, EA may modulate TJ, improving mucosal barrier function and ameliorating visceral hypersensitivity and pain.

Mast cells are widely distributed in the colonic mucosa and release substances like histamine, proteases, growth factors, prostaglandins, and cytokines. These mediators were reported to increase the excitability of enteric [66] and primary afferent neurons [67], leading to visceral hypersensitivity [42]. Previous studies suggested that mast cell activation correlated with the severity of abdominal pain [51; 68]. Furthermore, mast cell dysfunction compromises epithelial barrier function, which alters mucosal permeability, potentially leading to altered bowel function and pain [69]. A clinical study demonstrated that the number and activity of mucosal mast cells in IBS patients positively correlated with the degree of intestinal permeability [70]. Thus, from these preclinical and human studies, it is clear that mast cells are more likely to be activated in patients with IBS, releasing mediators known to interact with nerve endings and trigger pain. A recent research study reported that the EA at ST36 acupoint ameliorates post-inflammation rectal hypersensitivity by down-regulating mast cells activated nerve growth factor and tropomyosin receptor kinase A [13].

Whole-brain imaging techniques such as functional magnetic resonance imaging (fMRI) [71; 72] have been used to assess the mechanism of pain and suggested that changes in brain structure and functional connections (FCs) correlate with pain in IBS patients. Alteration of the serotonergic signaling in the emotional arousal circuit has been reported in both male and female IBS patients, which contributes to visceral hypersensitivity [73]. Moreover, IBS patients had alterations in grey matter in brain areas associated with cognitive and evaluative functions [74; 75]. Abnormal FCs in brain areas, including the hippocampus, occipital gyrus, and cerebellum, have been reported in IBS patients, and acupuncture treatment has improved these FCs [71; 76]. EA may exert an analgesic effect in IBS by enhancing the FC between the hippocampus and various brain regions and modulating the default mode and sensorimotor networks [72]. Thus, EA alleviates visceral pain in IBS model rats by regulating the peripheral, central, and endocrine systems, reducing inflammation, improving colon permeability, stabilizing mast cell function, and altering brain activity.

In conclusion, transcutaneous ST36 stimulation is as effective as direct ST36 stimulation and unilateral ST36 stimulation is comparable to bilateral stimulation. Development of a novel therapy using unilateral transcutaneous ST36 stimulation is warranted.

Ethics approval and consent to participate

In accordance with the National Institutes of Health guidelines, the Institutional Animal Care and Use Committee at the University of Michigan approved the use and care of animals in this study.

Consent for publication

Not applicable

Funding

Not applicable

Availability of data and materials

All data and materials are available upon request to the corresponding authors.

Competing interests

The authors declare no conflicts of interest.

Authors' contributions

M.J.A, T.Z., and J.D.C. conceived the study. M.J.A. and T.Z. performed the surgery, data acquisition, analysis, and interpretation and prepared the paper. J.W. and J.D.C. revised the manuscript. J.D.C. supervised the study.

Acknowledgments

The authors greatly appreciate the discussion and suggestions from all the lab members.

W.D. Chey, J. Kurlander, and S. Eswaran, Irritable bowel syndrome: a clinical review. JAMA 313 (2015) 949-58.
E.A. Mayer, H.J. Ryu, and R.R. Bhatt, The neurobiology of irritable bowel syndrome. Mol Psychiatry 28 (2023) 1451-1465.
M.J. Alam, and J.D.Z. Chen, Non-invasive neuromodulation: an emerging intervention for visceral pain in gastrointestinal disorders. Bioelectron Med 9 (2023) 27.
M.J. Alam, and J.D.Z. Chen, Electrophysiology as a Tool to Decipher the Network Mechanism of Visceral Pain in Functional Gastrointestinal Disorders. Diagnostics (Basel) 13 (2023).
A. Deiteren, A. de Wit, L. van der Linden, J.G. De Man, P.A. Pelckmans, and B.Y. De Winter, Irritable bowel syndrome and visceral hypersensitivity : risk factors and pathophysiological mechanisms. Acta Gastroenterol Belg 79 (2016) 29-38.
R.J. Bahar, B.S. Collins, B. Steinmetz, and M.E. Ament, Double-blind placebo-controlled trial of amitriptyline for the treatment of irritable bowel syndrome in adolescents. J Pediatr 152 (2008) 685-9.
L. Chen, S.J. Ilham, and B. Feng, Pharmacological Approach for Managing Pain in Irritable Bowel Syndrome: A Review Article. Anesth Pain Med 7 (2017) e42747.
M.D. Crowell, M.P. Jones, L.A. Harris, T.N. Dineen, V.A. Schettler, and K.W. Olden, Antidepressants in the treatment of irritable bowel syndrome and visceral pain syndromes. Curr Opin Investig Drugs 5 (2004) 736-42.
M. Grover, and D.A. Drossman, Psychotropic agents in functional gastrointestinal disorders. Curr Opin Pharmacol 8 (2008) 715-23.
J. Dz Chen, Y. Zhu, and Y. Wang, Emerging Noninvasive Neuromodulation Methods for Functional Gastrointestinal Diseases. J Transl Int Med 10 (2022) 281-285.
J. Fassov, L. Lundby, S. Laurberg, and K. Krogh, Sacral nerve modulation for irritable bowel syndrome: A randomized, double-blinded, placebo-controlled crossover study. Neurogastroenterol Motil 31 (2019) e13570.
J. Yin, and J.D. Chen, Noninvasive electrical neuromodulation for gastrointestinal motility disorders. Expert Rev Gastroenterol Hepatol 17 (2023) 1221-1232.
Y. Chen, J. Cheng, Y. Zhang, J.D.Z. Chen, and F.M. Seralu, Electroacupuncture at ST36 Relieves Visceral Hypersensitivity via the NGF/TrkA/TRPV1 Peripheral Afferent Pathway in a Rodent Model of Post-Inflammation Rectal Hypersensitivity. J Inflamm Res 14 (2021) 325-339.
Z. Huang, Z. Lin, C. Lin, H. Chu, X. Zheng, B. Chen, L. Du, J.D.Z. Chen, and N. Dai, Transcutaneous Electrical Acustimulation Improves Irritable Bowel Syndrome With Constipation by Accelerating Colon Transit and Reducing Rectal Sensation Using Autonomic Mechanisms. Am J Gastroenterol 117 (2022) 1491-1501.
P. Hu, K. Sun, H. Li, X. Qi, J. Gong, Y. Zhang, L. Xu, M. Lin, Y. Fan, and J.D.Z. Chen, Transcutaneous Electrical Acustimulation Improved the Quality of Life in Patients With Diarrhea-Irritable Bowel Syndrome. Neuromodulation 25 (2022) 1165-1172.
S. Siegel, E. Paszkiewicz, C. Kirkpatrick, B. Hinkel, and K. Oleson, Sacral nerve stimulation in patients with chronic intractable pelvic pain. J Urol 166 (2001) 1742-5.
E.D. Al-Chaer, M. Kawasaki, and P.J. Pasricha, A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology 119 (2000) 1276-85.
L. Jiang, N. Zhang, S. Zhang, and J.D. Chen, Sacral nerve stimulation with optimized parameters improves visceral hypersensitivity in rats mediated via the autonomic pathway. Mol Pain 15 (2019) 1744806919880651.
X. Jin, P. Gharibani, J. Yin, and J.D.Z. Chen, Neuro-Immune Modulation Effects of Sacral Nerve Stimulation for Visceral Hypersensitivity in Rats. Front Neurosci 15 (2021) 645393.
H. Jin, J. Guo, J. Liu, B. Lyu, R.D. Foreman, Z. Shi, J. Yin, and J.D.Z. Chen, Autonomically mediated anti-inflammatory effects of electrical stimulation at acupoints in a rodent model of colonic inflammation. Neurogastroenterol Motil 31 (2019) e13615.
L. Tu, P. Gharibani, J. Yin, and J.D.Z. Chen, Sacral nerve stimulation ameliorates colonic barrier functions in a rodent model of colitis. Neurogastroenterol Motil 32 (2020) e13916.
Y. Sun, Y. Tan, G. Song, and J.D. Chen, 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 26 (2014) 176-86.
J. Song, J. Yin, H.S. Sallam, T. Bai, Y. Chen, and J.D. Chen, Electroacupuncture improves burn-induced impairment in gastric motility mediated via the vagal mechanism in rats. Neurogastroenterol Motil 25 (2013) 807-e635.
J. Yin, J. Chen, and J.D. Chen, Ameliorating effects and mechanisms of electroacupuncture on gastric dysrhythmia, delayed emptying, and impaired accommodation in diabetic rats. Am J Physiol Gastrointest Liver Physiol 298 (2010) G563-70.
Y. Chen, Y. Guo, P. Gharibani, J. Chen, F.M. Selaru, and J.D.Z. Chen, Transitional changes in gastrointestinal transit and rectal sensitivity from active to recovery of inflammation in a rodent model of colitis. Sci Rep 11 (2021) 8284.
Y.S. Kim, and N. Kim, Sex-Gender Differences in Irritable Bowel Syndrome. J Neurogastroenterol Motil 24 (2018) 544-558.
N. Zhang, H. Zhang, L. Jiang, S. Zhang, J. Yin, L. Schramm, P.P. Pasricha, and J.D.Z. Chen, A novel method of sacral nerve stimulation for colonic inflammation. Neurogastroenterol Motil 32 (2020) e13825.
G.Y. Xu, M. Shenoy, J.H. Winston, S. Mittal, and P.J. Pasricha, P2X receptor-mediated visceral hyperalgesia in a rat model of chronic visceral hypersensitivity. Gut 57 (2008) 1230-7.
G.Y. Xu, J.H. Winston, M. Shenoy, S. Zhou, J.D. Chen, and P.J. Pasricha, The endogenous hydrogen sulfide producing enzyme cystathionine-beta synthase contributes to visceral hypersensitivity in a rat model of irritable bowel syndrome. Mol Pain 5 (2009) 44.
T.J. Ness, and G.F. Gebhart, Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat. Brain Res 450 (1988) 153-69.
H. Moon, Y. Ryu, I.S. Lee, and Y. Chae, Acupuncture treatment for functional gastrointestinal disorders: Identification of major acupoints using network analysis. Integr Med Res 12 (2023) 100970.
S. Liu, Z. Wang, Y. Su, L. Qi, W. Yang, M. Fu, X. Jing, Y. Wang, and Q. Ma, A neuroanatomical basis for electroacupuncture to drive the vagal-adrenal axis. Nature 598 (2021) 641-645.
M.J. Lu, Z. Yu, Y. He, Y. Yin, and B. Xu, Electroacupuncture at ST36 modulates gastric motility via vagovagal and sympathetic reflexes in rats. World J Gastroenterol 25 (2019) 2315-2326.
X.P. Ma, J. Hong, C.P. An, D. Zhang, Y. Huang, H.G. Wu, C.H. Zhang, and S. Meeuwsen, Acupuncture-moxibustion in treating irritable bowel syndrome: how does it work? World J Gastroenterol 20 (2014) 6044-54.
H.J. Chial, and M. Camilleri, Gender differences in irritable bowel syndrome. J Gend Specif Med 5 (2002) 37-45.
I. Midenfjord, C. Grinsvall, P. Koj, I. Carnerup, H. Tornblom, and M. Simren, Central sensitization and severity of gastrointestinal symptoms in irritable bowel syndrome, chronic pain syndromes, and inflammatory bowel disease. Neurogastroenterol Motil 33 (2021) e14156.
G.F. Gebhart, Pathobiology of visceral pain: molecular mechanisms and therapeutic implications IV. Visceral afferent contributions to the pathobiology of visceral pain. Am J Physiol Gastrointest Liver Physiol 278 (2000) G834-8.
E. Perna, J. Aguilera-Lizarraga, M.V. Florens, P. Jain, S.A. Theofanous, N. Hanning, J.G. De Man, M. Berg, B. De Winter, Y.A. Alpizar, K. Talavera, P. Vanden Berghe, M. Wouters, and G. Boeckxstaens, Effect of resolvins on sensitisation of TRPV1 and visceral hypersensitivity in IBS. Gut 70 (2021) 1275-1286.
D. Chu, P. Cheng, H. Xiong, J. Zhang, S. Liu, and X. Hou, Electroacupuncture at ST-36 relieves visceral hypersensitivity and decreases 5-HT3 receptor level in the colon in chronic visceral hypersensitivity rats. International Journal of Colorectal Disease 26 (2011) 569-574.
K.D. Xu, T. Liang, K. Wang, and D.A. Tian, Effect of pre-electroacupuncture on p38 and c-Fos expression in the spinal dorsal horn of rats suffering from visceral pain. Chin Med J (Engl) 123 (2010) 1176-81.
Q. Qi, F. Chen, W. Zhang, P. Wang, Y. Li, and X. Zuo, Colonic N-methyl-d-aspartate receptor contributes to visceral hypersensitivity in irritable bowel syndrome. J Gastroenterol Hepatol 32 (2017) 828-836.
Q. Zhou, D.D. Price, C.S. Callam, M.A. Woodruff, and G.N. Verne, Effects of the N-methyl-D-aspartate receptor on temporal summation of second pain (wind-up) in irritable bowel syndrome. J Pain 12 (2011) 297-303.
R. Sanoja, V. Tortorici, C. Fernandez, T.J. Price, and F. Cervero, Role of RVM neurons in capsaicin-evoked visceral nociception and referred hyperalgesia. Eur J Pain 14 (2010) 120 e1-9.
D. Kong, Y. Zhang, P. Gao, C. Pan, H. Deng, S. Xu, D. Tang, J. Xiao, Y. Jiao, W. Yu, and D. Wen, The locus coeruleus input to the rostral ventromedial medulla mediates stress-induced colorectal visceral pain. Acta Neuropathol Commun 11 (2023) 65.
D.B. Qi, and W.M. Li, Effects of electroacupuncture on expression of c-fos protein and N-methyl-D-aspartate receptor 1 in the rostral ventromedial medulla of rats with chronic visceral hyperalgesia. Zhong Xi Yi Jie He Xue Bao 10 (2012) 416-23.
P. Bercik, E.F. Verdu, and S.M. Collins, Is irritable bowel syndrome a low-grade inflammatory bowel disease? Gastroenterol Clin North Am 34 (2005) 235-45, vi-vii.
M. El-Salhy, D. Gundersen, J.G. Hatlebakk, and T. Hausken, Low-grade inflammation in the rectum of patients with sporadic irritable bowel syndrome. Mol Med Rep 7 (2013) 1081-5.
T.G. Dinan, E.M. Quigley, S.M. Ahmed, P. Scully, S. O'Brien, L. O'Mahony, S. O'Mahony, F. Shanahan, and P.W. Keeling, Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? Gastroenterology 130 (2006) 304-11.
T. Liebregts, B. Adam, C. Bredack, A. Roth, S. Heinzel, S. Lester, S. Downie-Doyle, E. Smith, P. Drew, N.J. Talley, and G. Holtmann, Immune activation in patients with irritable bowel syndrome. Gastroenterology 132 (2007) 913-20.
D.A. van Heel, I.A. Udalova, A.P. De Silva, D.P. McGovern, Y. Kinouchi, J. Hull, N.J. Lench, L.R. Cardon, A.H. Carey, D.P. Jewell, and D. Kwiatkowski, Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors. Hum Mol Genet 11 (2002) 1281-9.
C. Cremon, G. Carini, B. Wang, V. Vasina, R.F. Cogliandro, R. De Giorgio, V. Stanghellini, D. Grundy, M. Tonini, F. De Ponti, R. Corinaldesi, and G. Barbara, Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome. Am J Gastroenterol 106 (2011) 1290-8.
S. Mengzhu, Z. Yujie, S. Yafang, G. Jing, W. Yuhang, X. Chen, G.U. Dongmei, S. Jianhua, and P. Lixia, Electroacupuncture alleviates water avoidance stress-induced irritable bowel syndrome in mice by improving intestinal barrier functions and suppressing the expression of inflammatory cytokines. J Tradit Chin Med 43 (2023) 494-500.
L.V. Borovikova, S. Ivanova, M. Zhang, H. Yang, G.I. Botchkina, L.R. Watkins, H. Wang, N. Abumrad, J.W. Eaton, and K.J. Tracey, Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405 (2000) 458-62.
J.E. Ghia, P. Blennerhassett, H. Kumar-Ondiveeran, E.F. Verdu, and S.M. Collins, The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 131 (2006) 1122-30.
G. Goverse, M. Stakenborg, and G. Matteoli, The intestinal cholinergic anti-inflammatory pathway. J Physiol 594 (2016) 5771-5780.
V.A. Pavlov, H. Wang, C.J. Czura, S.G. Friedman, and K.J. Tracey, The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med 9 (2003) 125-34.
K.J. Tracey, The inflammatory reflex. Nature 420 (2002) 853-9.
J. Cheng, H. Shen, R. Chowdhury, T. Abdi, F. Selaru, and J.D.Z. Chen, Potential of Electrical Neuromodulation for Inflammatory Bowel Disease. Inflamm Bowel Dis 26 (2020) 1119-1130.
H. Jin, J. Liu, R.D. Foreman, J.D. Chen, and J. Yin, Electrical neuromodulation at acupoint ST36 normalizes impaired colonic motility induced by rectal distension in dogs. Am J Physiol Gastrointest Liver Physiol 309 (2015) G368-76.
M. Camilleri, K. Lasch, and W. Zhou, Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 303 (2012) G775-85.
M. Coeffier, R. Gloro, N. Boukhettala, M. Aziz, S. Lecleire, N. Vandaele, M. Antonietti, G. Savoye, C. Bole-Feysot, P. Dechelotte, J.M. Reimund, and P. Ducrotte, Increased proteasome-mediated degradation of occludin in irritable bowel syndrome. Am J Gastroenterol 105 (2010) 1181-8.
C. Martinez, M. Vicario, L. Ramos, B. Lobo, J.L. Mosquera, C. Alonso, A. Sanchez, M. Guilarte, M. Antolin, I. de Torres, A.M. Gonzalez-Castro, M. Pigrau, E. Saperas, F. Azpiroz, and J. Santos, The jejunum of diarrhea-predominant irritable bowel syndrome shows molecular alterations in the tight junction signaling pathway that are associated with mucosal pathobiology and clinical manifestations. Am J Gastroenterol 107 (2012) 736-46.
A. Nusrat, J.R. Turner, and J.L. Madara, Molecular physiology and pathophysiology of tight junctions. IV. Regulation of tight junctions by extracellular stimuli: nutrients, cytokines, and immune cells. Am J Physiol Gastrointest Liver Physiol 279 (2000) G851-7.
Y. Chen, Y. Zhao, D.N. Luo, H. Zheng, Y. Li, and S.Y. Zhou, Electroacupuncture Regulates Disorders of Gut-Brain Interaction by Decreasing Corticotropin-Releasing Factor in a Rat Model of IBS. Gastroenterol Res Pract 2019 (2019) 1759842.
X. Li, K. Ren, X. Hong, S. Guo, S. Yu, and S. Yang, Ameliorating effects of electroacupuncture on the low-grade intestinal inflammation in rat model of diarrhea-predominant irritable bowel syndrome. J Gastroenterol Hepatol 37 (2022) 1963-1974.
D.E. Reed, C. Barajas-Lopez, G. Cottrell, S. Velazquez-Rocha, O. Dery, E.F. Grady, N.W. Bunnett, and S.J. Vanner, Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons. J Physiol 547 (2003) 531-42.
A.D. Nozdrachev, G.N. Akoev, L.V. Filippova, N.O. Sherman, M.I. Lioudyno, and F.N. Makarov, Changes in afferent impulse activity of small intestine mesenteric nerves in response to antigen challenge. Neuroscience 94 (1999) 1339-42.
G. Barbara, V. Stanghellini, R. De Giorgio, C. Cremon, G.S. Cottrell, D. Santini, G. Pasquinelli, A.M. Morselli-Labate, E.F. Grady, N.W. Bunnett, S.M. Collins, and R. Corinaldesi, Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126 (2004) 693-702.
W.L. Hasler, G. Grabauskas, P. Singh, and C. Owyang, Mast cell mediation of visceral sensation and permeability in irritable bowel syndrome. Neurogastroenterol Motil 34 (2022) e14339.
H. Lee, J.H. Park, D.I. Park, H.J. Kim, Y.K. Cho, C.I. Sohn, W.K. Jeon, B.I. Kim, and S.W. Chae, Mucosal mast cell count is associated with intestinal permeability in patients with diarrhea predominant irritable bowel syndrome. J Neurogastroenterol Motil 19 (2013) 244-50.
K. Ma, Y. Liu, W. Shao, J. Sun, J. Li, X. Fang, J. Li, Z. Wang, and D. Zhang, Brain Functional Interaction of Acupuncture Effects in Diarrhea-Dominant Irritable Bowel Syndrome. Front Neurosci 14 (2020) 608688.
T. Zhao, L. Pei, H. Ning, J. Guo, Y. Song, J. Zhou, L. Chen, J. Sun, and Z. Mi, Networks Are Associated With Acupuncture Treatment in Patients With Diarrhea-Predominant Irritable Bowel Syndrome: A Resting-State Imaging Study. Front Hum Neurosci 15 (2021) 736512.
C.S. Hubbard, J. Hong, Z. Jiang, B. Ebrat, B. Suyenobu, S. Smith, N. Heendeniya, B.D. Naliboff, K. Tillisch, E.A. Mayer, and J.S. Labus, Increased attentional network functioning related to symptom severity measures in females with irritable bowel syndrome. Neurogastroenterol Motil 27 (2015) 1282-94.
D.A. Seminowicz, J.S. Labus, J.A. Bueller, K. Tillisch, B.D. Naliboff, M.C. Bushnell, and E.A. Mayer, Regional gray matter density changes in brains of patients with irritable bowel syndrome. Gastroenterology 139 (2010) 48-57 e2.
M. Zhao, Z. Hao, M. Li, H. Xi, S. Hu, J. Wen, Y. Gao, C.O. Antwi, X. Jia, Y. Yu, and J. Ren, Functional changes of default mode network and structural alterations of gray matter in patients with irritable bowel syndrome: a meta-analysis of whole-brain studies. Front Neurosci 17 (2023) 1236069.
W.C. Chu, J.C. Wu, D.T. Yew, L. Zhang, L. Shi, D.K. Yeung, D. Wang, R.K. Tong, Y. Chan, L. Lao, P.C. Leung, B.M. Berman, and J.J. Sung, Does acupuncture therapy alter activation of neural pathway for pain perception in irritable bowel syndrome?: a comparative study of true and sham acupuncture using functional magnetic resonance imaging. J Neurogastroenterol Motil 18 (2012) 305-16.

No competing interests reported.

Download PDF

Journal Publication

published 11 Nov, 2024

Read the published version in Bioelectronic Medicine →

Editorial decision: Revision requested
19 Aug, 2024
Reviews received at journal
16 Aug, 2024
Reviews received at journal
15 Aug, 2024
Reviewers agreed at journal
12 Aug, 2024
Reviews received at journal
11 Aug, 2024
Reviewers agreed at journal
08 Aug, 2024
Reviewers agreed at journal
01 Aug, 2024
Reviewers agreed at journal
01 Aug, 2024
Reviewers agreed at journal
29 Jul, 2024
Reviewers invited by journal
22 Jul, 2024
Editor assigned by journal
22 Jul, 2024
Submission checks completed at journal
22 Jul, 2024
First submitted to journal
18 Jul, 2024

You are reading this latest preprint version

Optimization of electrical stimulation modalities for treating visceral pain in a rodent model of irritable bowel syndrome

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Materials and Methods

Animals

Surgical procedures

Experiment design

Visceromotor reflex (VMR) response to CRD

Statistical analysis

Results

a) Acute BEA Improved Visceral Pain

b) Acute SNS did not Improve Visceral Pain

c) TEA via Surface Electrodes Improved Visceral Pain

d) Acute UEA Improved Visceral Pain

2. Acute BEA Improves Visceral Pain in Female Rats

Discussion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1