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Abstract

Chronic visceral pain stems from internal organs and is frequently associated with functional gastrointestinal disorders, like irritable bowel syndrome (IBS). Since the underlying mechanisms of visceral pain remain largely unclear, clinical management is often limited and ineffective. Comprehensive research into the pathogenesis of visceral pain, along with the development of personalized therapeutic strategies, is crucial for advancing treatment options. Studies suggest that imbalances in purinergic receptors and neural circuit function are closely linked to the onset of visceral pain. In this review, we will explore the etiology and pathological mechanisms underlying visceral pain, with a focus on ion channels, epigenetic factors, and neural circuits, using functional gastrointestinal disorders as case studies. Finally, we will summarize and evaluate emerging treatments and potential initiatives aimed at managing visceral pain.

Keywords

Chronic visceral pain irritable bowel syndrome ion channels epigenetic neural circuit clinical treatment

Introduction

According to epidemiological studies, over 20% of adults globally suffer from chronic visceral pain, making it one of the leading reasons for seeking medical care. Visceral pain arises from nociception in the visceral organs of the thoracic or abdominal cavity and is distinct from somatic pain.^1–3 It is commonly associated with conditions such as acute or chronic pancreatitis, gallstones, and gastrointestinal (GI) disorders. Pain related to GI issues like inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), functional dyspepsia (FD), and other digestive disorders poses significant challenges for both patients and healthcare providers.^4,5 The mechanisms behind chronic visceral pain remain largely unknown, with symptoms that are often difficult to localize and describe, complicating both diagnosis and treatment. Furthermore, individuals suffering from chronic visceral pain frequently experience comorbid emotional, sleep, and cognitive disturbances, including anxiety, depression, fear, insomnia, and cognitive impairment.^6,7 These issues can heighten the perception of pain, creating a vicious cycle that drives up healthcare costs and severely impacts quality of life.^7–10 For example, IBS alone accounts for more than $350 million in direct healthcare expenses annually in the United States.¹¹ The current treatment for visceral pain mainly involves traditional medications like non-steroidal anti-inflammatory drugs (NSAIDs) and opioids.¹² However, the ongoing opioid crisis further complicates pain management.¹³ Therefore, there is an urgent demand to investigate the underlying mechanisms of visceral pain and develop novel analgesic drugs and treatment strategies.

The pathological mechanisms of chronic visceral pain are highly diverse, involving multiple processes in both the peripheral and central nervous systems.² For instance, the upregulation of P2X3R expression in the dorsal root ganglion (DRG) and 5-HT_2B expression in the thalamic nucleus reuniens (Re) has been shown to contribute to visceral pain behavior.^14,15 In this review, we will summarize recent advances in understanding chronic visceral pain, focusing on ion channels, epigenetic factors, and neural circuits. We will also explore potential clinical diagnostic and therapeutic strategies, with the goal of offering new insights into drug development and treatments for chronic visceral pain.

Ion channels in chronic visceral pain

Ion channels are crucial in the development and persistence of chronic visceral pain, they modulate pain perception by regulating neuronal excitability and signal transmission. Key ion channels involved in chronic visceral pain include ligand-gated ion channels, transient receptor potential (TRP) channels, potassium channels, and various regulatory mechanisms governing these channels.

Purine and pyrimidine receptors (P receptors) are classified into two main categories: P1 and P2 receptors.^16,17 P1 receptors, also known as adenosine receptors, are G-protein-coupled receptors, while P2 receptors are divided into two subgroups: P2X and P2Y receptors. P2X receptors function as ligand-gated ion channels, whereas P2Y receptors are also G-protein-coupled. ATP plays a significant role in chronic visceral pain pathophysiology.^14,18,19 Burnstock²⁰ proposed that epithelial cells in tubular and sac-like organs release ATP in response to distension, which activates P2X3 receptors in the submucosal nerve plexus, transmitting pain signals to the central nervous system. Galligan and Bertrand²¹ demonstrated that ATP induces synaptic potentials in enteric neurons, while Ferguson et al.²² showed that increased bladder hydrostatic pressure enhances ATP release from bladder epithelial cells. This effect is inhibited by the P2 receptor antagonist suramin, further supporting ATP’s involvement in visceral pain signaling. Immunoreactivity of the P2X3 receptor has been observed in rat pelvic ganglion neurons, and P2X2 and P2X3 receptor immunoreactivities have been detected in guinea pig pelvic ganglion neurons.²³ Among P2X receptor subtypes, P2X4 homomers and P2X2/3 heteromers are thought to play a dominant role in chronic visceral pain.^24,25 Moreover, celiac ganglion neurons, which contain vagal afferent cell bodies, express functional P2X2 and P2X2/3 receptors, contributing to cardiovascular regulation and the transmission of angina.²³

TRP channels are a class of non-selective cation channels located on cell and intracellular organelle membranes.^26–30 The TRP channel family is a superfamily, and current research identifies seven subtypes. The TRP channel family is a large superfamily, with seven identified subtypes. These channels are involved in a variety of signaling functions, including maintaining ionic balance, regulating intracellular organelles and stroke, and modulating sensory transmission related to pain, itch, temperature, taste, and vision.^29,31–39 Subfamilies of TRP channels, such as TRPV, TRPA, TRPC, and TRPM, have been shown to contribute to visceral pain signaling.⁴⁰ In line with spinal afferent-mediated pain, most TRP channels are associated with pain perception. Approximately 75% of chronic visceral afferent fibers express TRPV1, which is activated by capsaicin, suggesting that TRPV1 plays a dominant role in visceral afferent signaling and chronic visceral pain.⁴¹ TRPA1 and TRPV1 channels coexist within visceral nociceptive fibers, working together to activate and modulate pain pathways. It has been confirmed that intestinal sensory neurons express multiple TRP channels. Research indicates that TRPA1, TRPV1, TRPV4, and TRPM8 may be co-expressed in the same neurons, acting synergistically in the nociceptive response. For example, in TRPA1 knockout mice, capsaicin no longer desensitizes colonic afferents, implying that TRPA1 channels are involved in the mechanical sensitivity mediated by TRPV1.⁴² Furthermore, studies show that nociceptor activation and chronic pancreatitis pain are driven by nerve growth factor, which upregulates TRPV1 channels.⁴³ Neurons expressing TRPV1 can exacerbate experimental pancreatitis induced by various stimuli.⁴⁴ However, TRPV1 knockout mice are still affected, suggesting that overlapping mechanisms exist within these neurons and other TRP channels may also play significant roles. Encouragingly, drugs targeting TRPV1 such as capsaicin patch (8%) and capsaicin creams have been successfully used in the clinic with promising analgesic results.^45,46 Interestingly, the antagonist of TRPV1, PAC-14028, was found to have favorable therapeutic effects on itch,^47,48 suggesting that TRPV1-related drugs have great translational potential for both pain and itch.

Acid-sensing ion channels (ASICs) are trimeric protein complexes consisting of combinations of different subunits and are non-selective cation channels that are mainly expressed in the peripheral and central nervous systems.^49,50 Previous studies have shown that ASIC1 is expressed at high levels in the spinal cord dorsal horn in visceral pain rats, and inhibition of ASIC1 significantly alleviated visceral pain behaviors, suggesting that ASIC1 mediates the development of visceral pain.^51,52 Increasing evidence confirms that Piezo2 is dominantly expressed in DRG neurons and produces somatic mechanical allodynia in the context of tissue inflammation and nerve injury.^53,54 Recent study has shown that ablation of Piezo2 relieves visceral pain responses, suggesting that Piezo2 plays a key regulatory role in visceral pain and is a potential therapeutic target.⁵⁵ Additionally, many other ion channels such as Kv7.2, Hv1 and BK are involved in pain regulation.^56–60 Gaining a better understanding of these mechanisms could support the development of novel treatments, such as drugs that target specific ion channels, offering more effective pain relief for patients.

Epigenetics related to chronic visceral pain

Epigenetics refers to stable, heritable changes in gene function that occur without changes to the DNA sequence. These changes include DNA methylation, chromatin remodeling, and the actions of non-coding RNAs (ncRNAs).^61–63 Recent research on epigenetic mechanisms in chronic visceral pain has primarily focused on histone acetylation and DNA methylation, providing new insights into gene expression regulation related chronic visceral pain.

There is growing body of evidence that both DNA methylation and demethylation play significant roles in modulating pain sensation in both the peripheral and central nervous systems.⁶⁴ DNA methylation is controlled by several enzymes, including DNA methyltransferases like DNMT1, DNMT3a, and DNMT3b, as well as DNMT2 and DNMT3L family members.⁶⁵ Other studies indicate that promoting interactions between transcription factors and demethylated gene promoters in the peripheral nervous system may impact neuropathic pain and gastric hypersensitivity.^66–68 Research also indicates that GATA binding protein 1 (GATA1)-mediated DNA demethylation at the P2X7 receptor (P2X7R) locus could play a key role in the development of chronic visceral pain, as observed in neonatal colonic inflammation (NCI) model rats.⁶⁹ This process may involve a direct interaction with the Ten-eleven translocation 3 (TET3) demethylase (see Figure 1). Furthermore, a repeated water avoidance stress (WAS) regimen in female rats has been shown to induce visceral pain hypersensitivity. This response is associated with increased acetylation of histone H3 in the spinal cord and an upregulation of mGlu2/3 receptor expression.⁷⁰

Figure 1.

Schematic representation of DNA methylation and demethylation processes in physiological and pathological conditions.

Notably, the intrathecal administration of the histone deacetylase (HDAC) inhibitor SHA has been shown to reverse stress-induced visceral pain hypersensitivity.⁷¹ Recent research also suggests that irritable bowel syndrome may have a heritable component due to epigenetic mechanisms. Specifically, the epigenetic regulation of pain-related genes in an adult IBS model is influenced by chronic stress experienced early in life. Pregnant rats subjected to intermittent heterotypic stress passed on heightened and persistent visceral pain sensitivity to their adult offspring when exposed to similar stress conditions.⁷² Brain-derived neurotrophic factor (BDNF) has been identified as a key pain mediator, with elevated BDNF levels in the lumbar spinal dorsal horn strongly correlating with increased pain sensitivity compared to control groups.⁷³ Blocking the BDNF receptor TrkB or administering BDNF-siRNA, which inhibits BDNF expression, reduced visceral pain hypersensitivity in offspring rats.^74,75 These changes in BDNF expression were linked to an mRNA isoform originating from the first exon of the ninth core promoter, which showed increased binding sites for RNA polymerase II and acetylated histone H3, while showing decreased binding sites for HDAC1. In adult rats, daily administration of HAT inhibitors like curcumin or ACA reversed BDNF upregulation and the associated visceral pain behaviors. This finding suggests that histone acetylation plays a significant role in stress-induced visceral pain hypersensitivity passed down to offspring.⁷⁶ Tran et al. also utilized the WAS-induced visceral pain model to investigate the role of epigenetic modifications in stress-induced IBS visceral pain. They discovered that a 7-day intraventricular injection of the HDAC inhibitor TSA effectively reduced stress-induced visceral pain hypersensitivity.⁷⁰

Additionally, there is increasing interest in the role of non-coding RNAs in the modulation of chronic pain, especially miRNAs.⁷⁷ Previous study has shown that miR-199 expression was significantly reduced in visceral pain model, whereas intraperitoneal injection of lenti-miR-199a precursors significantly alleviated visceral pain.⁷⁸ Similarly, miR-485 expression was significantly decreased in a rat model of visceral pain, and application of its corresponding agomir significantly alleviated visceral pain,⁵² suggesting that different miRNAs regulate visceral pain with some degree of resemblance. Therefore, targeted modulation of miRNAs expression is an effective potential therapy for visceral pain. Interestingly, miRNAs are capable of acting on ion channels thereby modulating visceral pain. Previous study has identified miR-1306-3P as a potential endogenous ligand for P2X3R, which modulates visceral pain by altering P2X3R activity.¹⁸ miR-485 also modulates visceral pain behavior by altering ASIC1 expression levels.⁵²

Excitingly, recent studies have revealed that epigenetic modifications – such as histone methylation, N6-methyladenosine (m⁶A) modification of RNA, and histone deacetylation – are critical in trigeminal neuropathic pain.^79–81 This highlights potential new therapeutic targets for treating neuropathic pain. However, it remains unclear whether similar epigenetic changes also influence visceral pain, which necessitates further investigation. While epigenetics offers exciting potential for studying chronic visceral pain, it also presents challenges. The complexity of epigenetic mechanisms requires the development of more precise experimental techniques to detect and explain relevant changes. Nevertheless, epigenetics provides new perspectives and tools for understanding chronic visceral pain. Future research is expected to uncover more detailed mechanisms, paving the way for personalized treatments and precision medicine in this field.

Neural circuits related to chronic visceral pain

Recent advances have greatly improved our understanding of the neural circuits and molecular mechanisms involved in chronic pain.^82–88 Multiple brain regions form neural circuits involved in the processing of pain signals.^89–91 However, the neural circuit mechanisms of chronic visceral pain remain largely unelucidated. Therefore, investigating the specific neural circuit mechanisms of visceral pain will hopefully provide suitable targets for the clinical treatment of chronic visceral pain.

Recent study evidenced that ventral part of lateral septum (LSV) was activated specifically by visceral pain stimulation and that optogenetic modulation of LSV glutamatergic neurons significantly altered visceral pain behavior in mice. This suggests that the LSV acts as a key regulatory center for visceral pain. Through viral tracing, it was found that the LSV forms a neural circuit with the paraventricular hypothalamus (PVH), and modulating this PVH-LSV circuit also affected visceral pain behaviors.⁹² Recent study has demonstrated that P2X3R plays a decisive role in the modulatory effects of the PVH-LSV circuit on visceral pain, and that this pathway loses its function in modulating visceral pain after knockdown of P2X3Rs.⁹³ Moreover, the PVH-ventral tegmental area (VTA) neural circuit plays a significant role in controlling chronic visceral pain. When corticotropin-releasing hormone (CRH) neurons in the PVH were inhibited, it blocked the production of tyrosine hydroxylase in the VTA, which had been triggered by colorectal distension.⁹⁴ Evidence shows that CRH neurons in the PVH receive inputs from both glutamatergic and gamma-aminobutyric acid (GABA) neurons in the anterior ventral part of the bed nucleus of the stria terminalis (avBNST), and these inputs together regulate visceral pain behaviors. Inhibiting the GABAergic neurons projecting from the BNST to the PVH worsened visceral pain, while activating this pathway alleviated it. Additionally, glutamatergic neurons in the avBNST send inputs to PVH CRH neurons.^95,96 Disruptions in the balance of excitatory and inhibitory inputs in the avBNST led to the overexcitation of PVH CRH neurons, which resulted in visceral pain behavior. Chemogenetic techniques were used to activate GABAergic neurons or inhibit glutamatergic neurons in the avBNST-PVH pathway, which reduced visceral pain in mice.⁹⁷ These studies highlight the importance of the PVH in developing and regulating visceral pain behavior, making it a key central hub for visceral pain regulation.

Previous studies have found that altered molecular expression in the anterior cingulate cortex (ACC) plays an important role in the processing of visceral pain, but the underlying neural circuitry mechanisms remain unclear.^8,98,99 However, accumulating evidence suggests that the ACC plays a dominant role in the neural circuits associated with visceral pain.^100–102 For instance, studies have demonstrated that the ACC responds more dramatically to colorectal distension stimulation in rats suffering from visceral pain, and functional magnetic resonance imaging (fMRI) data similarly show significant activation of the ACC in patients with irritable bowel syndrome.^100,103,104 The ACC receives a wide range of projections from other brain regions, forming neural circuits crucial for the modulation of chronic pain, including visceral pain.^{84,100,105,106} Recent findings have revealed that glutamatergic neurons in the claustrum (CL) project to the ACC and mediate visceral pain behavior, although these neurons may not regulate inflammatory pain.^100,107 Xu et al.¹⁰⁰ identified positive responses from glutamatergic neurons in both the CL and ACC to visceral pain, and viral tracing confirmed anatomical connections between the two regions. Manipulation of the CL-ACC pathway significantly altered visceral but not somatic pain in mice, suggesting that this circuit is specifically associated with visceral pain.¹⁰⁰

In addition to the PVH and ACC-related circuits, other brain regions such as the insular cortex, paraventricular thalamus, and reuniens (Re) have also been found to play important roles in the development of visceral pain behavior (see Figure 2).^{12,15,108,109} Therefore, investigating the neural circuit mechanisms of visceral pain and developing therapeutic strategies based on these circuits may offer promising approaches for clinical treatment of visceral pain.

Figure 2.

Summary schematic of neural circuits associated with visceral pain.

Analgesics associated with chronic visceral pain

Non-opioid analgesics

Acetaminophen has been widely used in the treatment of chronic pain, including chronic visceral pain, primarily due to its antipyretic and analgesic properties. These effects occur through central and peripheral non-opioid mechanisms. Acetaminophen is the preferred class I analgesic for mild to moderate pain, according to the World Health Organization (WHO) pain ladder. It is a well-tolerated painkiller that is considered safe for managing mild to moderate visceral pain. However, it is crucial to adhere to dosage guidelines to avoid the risk of liver damage from excessive intake. Unlike nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen lacks anti-inflammatory effects.¹¹⁰ NSAIDs have been reported to offer significant analgesic relief, especially in conditions like renal colic. However, due to their gastrointestinal side effects, including the potential for causing peptic ulcers and other lesions, NSAIDs are less commonly used for general visceral pain in clinical practice. In summary, acetaminophen is considered superior to NSAIDs for treating chronic visceral pain because it avoids the gastrointestinal side effects associated with NSAIDs, while maintaining a favorable safety profile. Acetaminophen can be used continuously when long-term analgesia is required.

Opioid analgesics

Opioids are frequently prescribed for patients with moderate to severe pain who do not respond to non-opioid treatments. They are also used for chronic visceral pain. Research indicates that morphine can increase the threshold for esophageal mechanical pain. In experimental pain tests involving patients with chronic pancreatitis, oxycodone was found to be more effective than morphine, as it raised both mechanical and thermal pain thresholds.¹¹¹ Additionally, current treatments can target peripheral kappa-opioid receptors (KORs). For example, the peripherally selective KOR agonist acimalalindol has been shown to alleviate pain caused by colonic dilation in people with irritable bowel syndrome.^112–114 Conversely, the loss of peripheral μ-opioid receptors (MORs) or the neurons expressing MORs reduces thermal tolerance, but does not affect the development or persistence of anti-allodynic tolerance or morphine-induced mechanical allodynia.¹¹⁵ While opioids are a valuable and cost-effective option for treating organic visceral pain, their role in managing functional visceral diseases remains unclear. Opioids are associated with several serious side effects, including respiratory depression, motor and cognitive impairment, sedation, and the development of tolerance. Long-term use may also lead to opioid-induced hyperalgesia, where patients become more sensitive to pain. Additionally, chronic intractable pain can lead to changes in the central pain pathways, such as central sensitization, making opioid therapy less effective.¹¹⁶

Adjunctive analgesics

Many patients experience significant relief from standard analgesic interventions, but a considerable number continue to suffer from pain. To address this, incorporating adjunctive analgesics into a stepwise approach for managing chronic visceral pain is often effective. Introducing adjunctive analgesics early in the pain management process, especially when central sensitization manifests as hyperalgesia or touch-induced pain, can be crucial. At present, tricyclic antidepressants and GABA analogs are mostly utilized in clinical settings. Pregabalin and Gabapentin, two GABA analogs, have shown effectiveness in preclinical models of visceral hypersensitivity.^117–119 Pregabalin and Gabapentin have been shown to reduce experimental pain in chronic pancreatitis and IBS.¹²⁰ Additionally, other medications, such as tricyclic antidepressants (TCAs), selective serotonergic reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) are also employed in the treatment of chronic visceral pain,¹¹⁴ particularly for functional disorders. Adjunctive analgesics play a crucial role in managing visceral pain. It is essential to begin treatment with these adjuvants as early as possible, particularly when central sensitization is present.

Unconventional drug therapies

New analgesic drugs may soon be developed based on the growing understanding of the pain mechanisms of functional and organic visceral pain disorders. TRPV1 is a non-selective ion channel that can be activated by capsaicin, low pH, and nociceptive thermal stimuli. It is an integrator of pain stimuli, and as a result, TRPV1 antagonists have received increasing attention as novel analgesic agents.¹²¹ Consequently, TRPV1 antagonists have gained significant attention as potential novel analgesics. The analgesic effects of TRPV1 antagonists have been demonstrated in several inflammatory diseases, including acute colitis and chronic pancreatitis (CP), where TRPV1 receptor sensitization may enhance peripheral sensitization.^2,122,123 Linaclotide is a guanylate cyclase-C agonist primarily used to treat constipation-type IBS.¹²⁴ By activating guanylate cyclase-C, it promotes the secretion of chloride and bicarbonate into the intestinal lumen, leading to increased fluid secretion and enhanced intestinal peristalsis. In addition to its laxative effect, recent studies have shown that linaclotide also exerts analgesic effects by blocking colonic nociceptors—a mechanism primarily validated in animal and in vitro models. Phase III clinical trials have further confirmed linaclotide’s analgesic benefits in patients with constipation-predominant IBS.¹²⁵ Our previous study showed that P2X7R antagonists effectively suppressed chronic visceral pain behavior and inhibited spinal synaptic transmission.⁶⁹ Moreover, studies found that the P2X3 receptor inhibitor, TNP-ATP, can block acetic acid-induced abdominal spasms in rats and reduce visceral hypersensitivity caused by neonatal colon inflammation. These findings suggest that P2X receptors may serve as promising targets for novel analgesic therapies.^126,127

Non-invasive brain stimulation in chronic visceral pain

Non-invasive brain stimulation (NIBS) has made significant strides in the treatment of chronic visceral pain.¹²⁸ Traditional treatment methods always have limited effectiveness and come with a higher risk of side effects, making NIBS an appealing alternative. As an emerging treatment modality, NIBS has garnered considerable attention. Studies have shown that both transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) hold great promise for treating chronic visceral pain.¹²⁹ TMS generates magnetic fields in specific brain areas to modulate neuronal activity, thereby alleviating pain.^128,130,131 tDCS, on the other hand, alters the excitability of the cerebral cortex by applying a weak direct current to the scalp, aiming to relieve pain.¹³² A recent clinical trial revealed that patients treated with TMS reported significant improvements in pain scores and quality of life.¹³³ Researchers have found that by precisely targeting specific brain regions associated with visceral pain, the regulation of pain activity can be more effective. Similarly, tDCS has shown positive effects in managing visceral pain caused by chronic pancreatitis, with patients reporting significant reductions in pain levels without notable side effects.¹³⁴ Beyond TMS and tDCS, other NIBS technologies are being continuously developed. For instance, transcranial random noise stimulation (tRNS) and transcranial alternating current stimulation (tACS) are emerging approaches that are gradually being applied to the treatment of chronic visceral pain.¹³⁵ Interestingly, Zhou et al.¹³⁶ demonstrated that sound induces analgesia through corticothalamic pathway and found that the analgesic effects of sound depended on a low (5-decibel) signal-to-noise ratio relative to ambient noise. Although the applicability of sound analgesia to visceral pain remains unclear, this provides an essential insight into the development of non-invasive brain stimulation for the treatment of visceral pain. These techniques modulate brain activity through different mechanisms, offering patients a wider range of treatment options. Additionally, accumulating evidence suggests that non-pharmacological therapies such as psychotherapy and dietary adjustment show considerable potential in the treatment of chronic visceral pain.^137–139 Previous study has demonstrated that the combined employment of psychotherapy and drugs is significantly more effective in the treatment of IBS than drugs alone,¹³⁷ suggesting that psychotherapy may be a catalyst for the conventional pharmacological treatment of IBS. As an essential regulator of normal gut function, the gut microbiota is considered a key peripheral factor in the pathophysiology of chronic visceral pain. As diet is a major determinant of the configuration of the gut microbiota, it is increasingly recognized that the interaction between diet and microbiota plays an essential role in the development of visceral pain, and that dietary adjustment is an effective way to alleviate visceral pain.¹⁴⁰ In addition, it has been shown that gastrointestinal hypersensitivity is also caused by the activation of enterochromaffin (EC) cells, which are rare excitable, serotonergic neuroendocrine cells in the gut epithelium.^141,142 Additionally, perturbing EC cell activity promoted anxiety-like behaviors which normalized after blockade of serotonergic signaling,⁷ suggesting that anxiety relief by targeting serotonergic signaling pathways is a potential modality for the treatment of visceral pain. The combination of non-invasive brain stimulation technologies with non-pharmacological therapies contributes to a multi-dimensional pain management framework.

Despite the promising potential of NIBS technologies, several challenges remain. Determining optimal stimulation parameters, improving individualized treatment approaches, and validating long-term efficacy are areas that need further research. Addressing these challenges will be crucial for the broader application of NIBS in chronic visceral pain treatment. In conclusion, NIBS technologies bring new hope for the management of chronic visceral pain. With ongoing research and technological advancements, these techniques hold great potential to deliver significant clinical benefits, improving the quality of life for more patients.

Conclusions

The pathology of visceral pain is highly complex, and its exact mechanisms have not yet been fully elucidated. In this review, we analyze the intrinsic mechanisms of visceral pain from various perspectives, including ion channels, epigenetics, neural circuits, analgesics and non-invasive brain stimulation with the goal of offering new insights into potential treatments (see Figure 3). Historically, much research on the signaling and regulatory mechanisms of visceral pain has focused on the peripheral and spinal cord levels. However, the rapid advancements in neural circuit studies have provided fresh perspectives on the brain’s role in visceral pain. Despite this progress, the specific molecular targets and neural circuits related to visceral pain remain incompletely understood, presenting significant challenges for developing targeted treatments. Encouragingly, the rapid development of modern neuroscience techniques has made function-dependent labeling and modulation tools increasingly precise. For example, the “targeted recombination in active populations” (TRAP) labeling system and the “Tet-off” viral labeling system enable the specific manipulation of neurons activated by visceral pain.⁹³ These tools hold great promise for future studies aimed at identifying molecular targets and neural circuits directly associated with visceral pain. In conclusion, significant progress has been made in the development of therapeutic drugs and approaches for visceral pain. However, limitations and challenges remain, underscoring the need for further research and exploration in this field.

Figure 3.

Summary schematic of ion channels, epigenetics, neural circuits, analgesic drugs, and noninvasive brain stimulation associated with visceral pain.

Footnotes

Author contribution

Y-C.L,F-C.Z and T-W.X collected data and prepared the manuscript. R-X.W,H-H.Z,Q-Q.C,S-F.H,Y.G and R.L revised the manuscript. G-Y.X designed the research plan,supervised writing and finalized the manuscript. All the authors have read and approved the paper.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research,authorship,and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research,authorship,and/or publication of this article: This work was supported by grants from National Natural Science Foundation of China (82401454,82470573,81920108016 and 32230041),Postdoctoral Fellowship Program of CPSF under Grant Number GZC20231890,Jiangsu Provincial Department of Science and Technology (BE2023710) and the Priority Academic Program Development of Jiangsu Higher Education Institutions of China. The funders had no role in the study design,data collection and analysis,decision to publish,or preparation of the manuscript.

ORCID iDs

Shufen Hu

Guang-Yin Xu

References

Grundy

Erickson

Brierley

. Visceral pain. Annu Rev Physiol 2019; 81: 261–284.

Ford

Vanner

Kashyap

Nasser

. Chronic visceral pain: new peripheral mechanistic insights and resulting treatments. Gastroenterology 2024; 166: 976–994.

Moloney

O’Mahony

Dinan

Cryan

. Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities. Front Psychiatry 2015; 6: 15.

Sinopoulou

Gordon

Dovey

Akobeng

. Interventions for the management of abdominal pain in ulcerative colitis. Cochrane Database Syst Rev 2021; 7: CD013589.

Drossman

. Functional gastrointestinal disorders: history, pathophysiology, clinical features and Rome IV. Gastroenterology. Epub ahead of print 19 February 2016. DOI: 10.1053/j.gastro.2016.02.032.

Zhang

. Enterochromaffin cell: friend or foe for human health? Neurosci Bull 2023; 39: 1732–1734.

Bayrer

Castro

Venkataraman

Touhara

Rossen

Morrie

Maddern

Hendry

Braverman

Garcia-Caraballo

Schober

Brizuela

Castro Navarro

Bueno-Silva

Ingraham

Brierley

Julius

. Gut enterochromaffin cells drive visceral pain and anxiety. Nature 2023; 616: 137–142.

Liu

Shao

Song

Chen

Dong

Zhang

. The microglial innate immune receptors TREM-1 and TREM-2 in the anterior cingulate cortex (ACC) drive visceral hypersensitivity and depressive-like behaviors following DSS-induced colitis. Brain Behav Immun 2023; 112: 96–117.

Benson

Rebernik

Pastoors

Brinkhoff

Wegner

Elsenbruch

Engler

. Impact of acute inflammation on the extinction of aversive gut memories. Brain Behav Immun 2020; 88: 294–301.

10.

Lamvu

Ouyang

Rapkin

. A review of chronic pelvic pain in women-reply. JAMA 2021; 326: 2207–2208.

11.

Congly

Novak

Belletrutti

Raman

Woo

Andrews

Nasser

. Epidemiologic burden and treatment of chronic symptomatic functional bowel disorders in the United States: a nationwide analysis. Gastroenterology 2021; 160: 88–98.e4.

12.

Dou

Zhou

Sun

Liu

Hao

. Modulation of visceral pain by brain nuclei and brain circuits and the role of acupuncture: a narrative review. Front Neurosci 2023; 17: 1243232.

13.

LeBrett

Chang

. Prescription pain medications for disorders of gut-brain interaction: comparing usage patterns with clinical practice recommendations. Neurogastroenterol Motil 2023; 35: e14645.

14.

Sun

Song

Zhang

. Adult stress promotes purinergic signaling to induce visceral pain in rats with neonatal maternal deprivation. Neurosci Bull 2020; 36: 1271–1280.

15.

Chen

Dai

Wang

. Thalamic nucleus reuniens glutamatergic neurons mediate colorectal visceral pain in mice via 5-HT_2B receptors. Neurosci Bull 2024; 40(10): 1421–1433.

16.

Jacobson

Jarvis

Williams

. Purine and pyrimidine (P2) receptors as drug targets. J Med Chem 2002; 45: 4057–4093.

17.

Ralevic

Burnstock

. Receptors for purines and pyrimidines. Pharmacol Rev 1998; 50: 413–492.

18.

Wang

Zhang

Zhu

. miR-1306-3p directly activates P2X3 receptors in primary sensory neurons to induce visceral pain in rats. Pain 2023; 164: 1555–1565.

19.

Defaye

Abdullah

Iftinca

Hassan

Agosti

Zhang

Cumenal

Zamponi

Altier

. Gut-innervating TRPV1+ neurons drive chronic visceral pain via microglial P2Y12 receptor. Cell Mol Gastroenterol Hepatol 2022; 13: 977–999.

20.

Burnstock

. Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci 2001; 22: 182–188.

21.

Galligan

Bertrand

. ATP mediates fast synaptic potentials in enteric neurons. J Neurosci 1994; 14: 7563–7571.

22.

Ferguson

Kennedy

Burton

. ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes — a possible sensory mechanism? J Physiol 1997; 505(Pt 2): 503–511.

23.

Dunn

Zhong

Burnstock

. P2X receptors in peripheral neurons. Prog Neurobiol 2001; 65: 107–134.

24.

Tang

Chen

Liu

Sun

Chen

Huang

Ai-Qin

Chen

Lin

. Spinal P2X4 receptors involved in visceral hypersensitivity of neonatal maternal separation rats. Purinergic Signal 2023; 19: 113–122.

25.

Luo

Zhang

. Role and therapeutic target of P2X2/3 receptors in visceral pain. Neuropeptides 2023; 101: 102355.

26.

Zhang

Pan

Wang

. TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases. Signal Transduct Target Ther 2023; 8: 261.

27.

Wang

Chen

. Functional changes in astrocytes lead to cognitive deficits after social deprivation. Neurosci Bull 2024; 40: 547–549.

28.

Dai

Hao

Zheng

. High magnesium promotes the recovery of binocular vision from amblyopia via TRPM7. Neurosci Bull 2024; 40: 1245–1260.

29.

Zong

Feng

Cicchetti

Yue

. TRP channels in stroke. Neurosci Bull 2024; 40: 1141–1159.

30.

Cao

. Neural mechanisms underlying the coughing reflex. Neurosci Bull 2023; 39: 1823–1839.

31.

Numata

Takahashi

Inoue

. “TRP inflammation” relationship in cardiovascular system. Semin Immunopathol 2016; 38: 339–356.

32.

Xing

Wei

Liu

Wang

Sui

Wang

Zhu

Fei

Jiang

Zhang

Wang

Guo

Cao

Wang

. Autophagy inhibition mediated by MCOLN1/TRPML1 suppresses cancer metastasis via regulating a ROS-driven TP53/p53 pathway. Autophagy 2022; 18: 1932–1954.

33.

de Almeida

Bernardes

Trevisan

. TRP channels in cancer pain. Eur J Pharmacol 2021; 904: 174185.

34.

Moore

Gupta

Jordt

Chen

Liedtke

. Regulation of pain and itch by TRP channels. Neurosci Bull 2018; 34: 120–142.

35.

Rosenbaum

Morales-Lázaro

Islas

. TRP channels: a journey towards a molecular understanding of pain. Nat Rev Neurosci 2022; 23: 596–610.

36.

Voets

Droogmans

Wissenbach

Janssens

Flockerzi

Nilius

. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 2004; 430: 748–754.

37.

Venkatachalam

Montell

. TRP channels. Annu Rev Biochem 2007; 76: 387–417.

38.

Zhang

Dong

Cao

Huang

. A new potential strategy for treatment of ischemic stroke: targeting TRPM2-NMDAR Association. Neuroscience bulletin 2023; 39: 703–706.

39.

Kim

Jang

Kim

Lee

Kim

Vang

Lee

. Mitochondrial reactive oxygen species elicit acute and chronic itch via transient receptor potential canonical 3 activation in mice. Neurosci Bull 2022; 38: 373–385.

40.

Zhang

Jones

Brody

Costa

Brookes

. Thermosensitive transient receptor potential channels in vagal afferent neurons of the mouse. Am J Physiol Gastrointest Liver Physiol 2004; 286: G983–G991.

41.

Brierley

Jones

3rd Gebhart

Blackshaw

. Splanchnic and pelvic mechanosensory afferents signal different qualities of colonic stimuli in mice. Gastroenterology 2004; 127: 166–178.

42.

Brierley

Hughes

Page

Kwan

Martin

O’Donnell

Cooper

Harrington

Adam

Liebregts

Holtmann

Corey

Rychkov

Blackshaw

. The ion channel TRPA1 is required for normal mechanosensation and is modulated by algesic stimuli. Gastroenterology 2009; 137: 2084–2095.e3.

43.

Zhu

Colak

Shenoy

Liu

Pai

Mehta

Pasricha

. Nerve growth factor modulates TRPV1 expression and function and mediates pain in chronic pancreatitis. Gastroenterology 2011; 141: 370–377.

44.

Romac

McCall

Humphrey

Heo

Liddle

. Pharmacologic disruption of TRPV1-expressing primary sensory neurons but not genetic deletion of TRPV1 protects mice against pancreatitis. Pancreas 2008; 36: 394–401.

45.

Baranidharan

Das

Bhaskar

. A review of the high-concentration capsaicin patch and experience in its use in the management of neuropathic pain. Ther Adv Neurol Disord 2013; 6: 287–297.

46.

Anand

Bley

. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth 2011; 107: 490–502.

47.

Yun

Seo

Jeong

Bae

Jang

Lee

Kim

Shin

Woo

Lee

Lim

Park

. TRPV1 antagonist can suppress the atopic dermatitis-like symptoms by accelerating skin barrier recovery. J Dermatol Sci 2011; 62: 8–15.

48.

Park

Kim

Lee

Won

Park

Chung

Lee

Jung

Nam

Choi

Park

Kim

Park

. Asivatrep, a TRPV1 antagonist, for the topical treatment of atopic dermatitis: Phase 3, randomized, vehicle-controlled study (CAPTAIN-AD). J Allergy Clin Immunol 2022; 149: 1340–1347.e4.

49.

Lynagh

Mikhaleva

Colding

Glover

Pless

. Acid-sensing ion channels emerged over 600 Mya and are conserved throughout the deuterostomes. Proc Natl Acad Sci U S A 2018; 115: 8430–8435.

50.

Yoder

Yoshioka

Gouaux

. Gating mechanisms of acid-sensing ion channels. Nature 2018; 555: 397–401.

51.

Tian

Zhang

Sha

. Upregulation of spinal ASIC1 and NKCC1 expression contributes to chronic visceral pain in rats. Front Mol Neurosci 2020; 13: 611179.

52.

Weng

Wang

Zhang

. Upregulation of spinal ASIC1 by miR-485 mediates enterodynia in adult offspring rats with prenatal maternal stress. CNS Neurosci Ther 2021; 27: 244–255.

53.

Murthy

Loud

Daou

Marshall

Schwaller

Kuhnemund

Francisco

Keenan

Dubin

Lewin

Patapoutian

. The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice. Sci Transl Med 2018; 10: eaat9897.

54.

Szczot

Liljencrantz

Ghitani

Barik

Lam

Thompson

Bharucha-Goebel

Saade

Necaise

Donkervoort

Foley

Gordon

Case

Bushnell

Bonnemann

Chesler

. PIEZO2 mediates injury-induced tactile pain in mice and humans. Sci Transl Med 2018; 10: eaat9892.

55.

Xie

Feng

Hibberd

Chen

Zhao

Zang

Yang

Chen

Brookes

Spencer

. Piezo2 channels expressed by colon-innervating TRPV1-lineage neurons mediate visceral mechanical hypersensitivity. Neuron 2023; 111: 526–538.e4.

56.

Zhan

Zhang

Ren

Zhao

Zang

Cao

. TET1 participates in complete Freund’s adjuvant-induced trigeminal inflammatory pain by regulating Kv7.2 in a mouse model. Neurosci Bull 2024; 40: 707–718.

57.

Shen

Luo

Liao

Zuo

Jiang

. Role of the voltage-gated proton channel Hv1 in nervous systems. Neurosci Bull 2023; 39: 1157–1172.

58.

Fan

Chen

Guan

Tang

Chen

Lin

. Blockade of BK channels attenuates chronic visceral hypersensitivity in an IBS-like rat model. Mol Pain 2021; 17: 17448069211040364.

59.

Lei

Xie

Cao

Zhang

Xiao

Tian

Zhu

Zhang

. Parkin inhibits static mechanical pain by suppressing membrane trafficking of mechano-transducing ion channel TACAN. Neurosci Bull 2022; 38: 429–434.

60.

Cherninskyi

Storozhuk

Maximyuk

Kulyk

Krishtal

. Triggering of major brain disorders by protons and ATP: the role of ASICs and P2X receptors. Neurosci Bull 2023; 39: 845–862.

61.

Kular

Jagodic

. Epigenetic insights into multiple sclerosis disease progression. J Intern Med 2020; 288: 82–102.

62.

Ren

Tang

Zhang

Guo

Cui

Wang

Xie

Chen

Zhang

Han

Chu

Liang

Zhao

Huang

Liu

Chen

. The role of KDM2A and H3K36me2 demethylation in modulating MAPK signaling during neurodevelopment. Neurosci Bull 2024; 40: 1076–1092.

63.

Zhou

Zhang

. Chromatin remodeling factor SMARCA5 is essential for hippocampal memory maintenance via metabolic pathways in mice. Neurosci Bull 2023; 39: 1087–1104.

64.

Xiong

Wyns

Campenhout

Hendrix

De Bruyne

Godderis

Schabrun

Nijs

Polli

. Epigenetic landscapes of pain: DNA methylation dynamics in chronic pain. Int J Mol Sci 2024; 25: 8324.

65.

Lyko

. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet 2018; 19: 81–92.

66.

Jiang

Shi

Zhang

Cao

Gao

. Promoted interaction of C/EBPα with demethylated Cxcr3 gene promoter contributes to neuropathic pain in mice. J Neurosci 2017; 37: 685–700.

67.

Zhang

Zhou

Wang

Chen

Xiao

Huang

Jiang

. Promoted interaction of nuclear factor-κB with demethylated cystathionine-β-synthetase gene contributes to gastric hypersensitivity in diabetic rats. J Neurosci 2013; 33: 9028–9038.

68.

Wang

Zhang

Zhou

Jiang

. Epigenetic upregulation of acid-sensing ion channel 1 contributes to gastric hypersensitivity in adult offspring rats with prenatal maternal stress. Pain 2020; 161: 989–1004.

69.

Zhang

. Targeting GATA1 and p2x7r locus binding in spinal astrocytes suppresses chronic visceral pain by promoting DNA demethylation. Neurosci Bull 2022; 38: 359–372.

70.

Greenwood-Van Meerveld

Johnson

. Stress-induced chronic visceral pain of gastrointestinal origin. Front Syst Neurosci 2017; 11: 86.

71.

Cao

Bai

Karpowicz

Traub

. EXPRESS: histone hyperacetylation modulates spinal type II metabotropic glutamate receptor alleviating stress-induced visceral hypersensitivity in female rats. Mol Pain 2016; 12: 1744806916660722.

72.

Chen

Saliuk

Bazhanov

Winston

. Estrogen and serotonin enhance stress-induced visceral hypersensitivity in female rats by up-regulating brain-derived neurotrophic factor in spinal cord. Neurogastroenterol Motil 2021; 33: e14117.

73.

Zuo

Zhao

Chen

Yang

Dong

Wang

. Brain-derived neurotrophic factor contributes to abdominal pain in irritable bowel syndrome. Gut 2012; 61: 685–694.

74.

Winston

Sarna

. Chronic prenatal stress epigenetically modifies spinal cord BDNF expression to induce sex-specific visceral hypersensitivity in offspring. Neurogastroenterol Motil 2014; 26: 715–730.

75.

Fan

Tang

Dai

Cao

Sun

Chen

Lin

. Blockade of BDNF signalling attenuates chronic visceral hypersensitivity in an IBS-like rat model. Eur J Pain 2020; 24: 839–850.

76.

Qin

Tan

Sun

. Effect of retrograde colonic electrical stimulation on colonic transit and stress-induced visceral hypersensitivity in rats with irritable bowel syndrome. Asian Pac J Trop Med 2017; 10: 827–832.

77.

Mauceri

. Role of epigenetic mechanisms in chronic pain. Cells 2022; 11: 2613.

78.

Zhou

Yang

Larson

Basra

Merwat

Tan

Croce

Verne

. Decreased miR-199 augments visceral pain in patients with IBS through translational upregulation of TRPV1. Gut 2016; 65: 797–805.

79.

Tao

Zhang

Jin

Hua

Liu

Huang

Sun

Jiang

Snutch

Jiang

Tao

. Epigenetic regulation of beta-endorphin synthesis in hypothalamic arcuate nucleus neurons modulates neuropathic pain in a rodent pain model. Nat Commun 2023; 14: 7234.

80.

Huang

Zhang

Wang

Tao

Sun

Jiang

Tao

. FOXD3-mediated transactivation of ALKBH5 promotes neuropathic pain via m⁶A-dependent stabilization of 5-HT3A mRNA in sensory neurons. Proc Natl Acad Sci U S A 2024; 121: e2312861121.

81.

Cao

Sun

Huang

Jiang

Snutch

Zhang

Tao

. Histone methylation-mediated microRNA-32-5p down-regulation in sensory neurons regulates pain behaviors via targeting Cav3.2 channels. Proc Natl Acad Sci U S A 2022; 119: e2117209119.

82.

Tang

Liu

Zhou

Cao

Weng

Zhang

. Green light analgesia in mice is mediated by visual activation of enkephalinergic neurons in the ventrolateral geniculate nucleus. Sci Transl Med 2022; 14: eabq6474.

83.

Wang

Dong

Feng

Huang

Yang

Gao

Shen

Lin

Cao

Lian

Chen

Yan

. Incerta-thalamic circuit controls nocifensive behavior via cannabinoid type 1 receptors. Neuron 2020; 107: 538–551.e7.

84.

Tang

Dong

Huang

Xiong

Xue

Liu

Zhu

Zhang

. A neural circuit for the suppression of feeding under persistent pain. Nat Metab 2022; 4: 1746–1755.

85.

Yue

Liu

Zhang

Cui

Liu

Wan

. Dynamic changes of the infralimbic cortex and its regulation of the prelimbic cortex in rats with chronic inflammatory pain. Neurosci Bull 2024; 40: 872–886.

86.

Zhang

Chen

Wang

Yao

Chen

. Tau accumulation in the spinal cord contributes to chronic inflammatory pain by upregulation of IL-1β and BDNF. Neurosci Bull 2024; 40: 466–482.

87.

Xian

Guo

Liu

Zhang

Zhao

Xie

Zhang

Cong

. Peripheral BDNF regulates somatosensory-sympathetic coupling in brachial plexus avulsion-induced neuropathic pain. Neurosci Bull 2023; 39: 1789–1806.

88.

Zhang

Xue

Zhao

Meng

Zhang

. Activation of cannabinoid receptor 1 in GABAergic neurons in the rostral anterior insular cortex contributes to the analgesia following common peroneal nerve ligation. Neurosci Bull 2023; 39: 1348–1362.

89.

Guo

Zheng

Chen

Xiong

Wang

Lin

Zhang

Manyande

Wang

Peng

. Preoperative acute sleep deprivation causes postoperative pain hypersensitivity and abnormal cerebral function. Neurosci Bull 2022; 38: 1491–1507.

90.

Zhang

Geng

Chen

Wang

Qiu

Fan

Zhu

Yang

Chen

Zhou

Fan

Bai

Xing

Feng

Wang

Chen

Liang

Cao

Kaang

Zhuo

Chen

. Glutamatergic synapses from the insular cortex to the basolateral amygdala encode observational pain. Neuron 2022; 110: 1993–2008.e6.

91.

Gan

Gangadharan

Liu

Korber

Tan

Oswald

Kang

Martin-Cortecero

Mannich

Groh

Kuner

Wieland

Kuner

. Layer-specific pain relief pathways originating from primary motor cortex. Science 2022; 378: 1336–1343.

92.

Wang

. A paraventricular hypothalamic nucleus input to ventral of lateral septal nucleus controls chronic visceral pain. Pain 2023; 164: 625–637.

93.

Zhang

Weng

Gao

. Distinct circuits and molecular targets of the paraventricular hypothalamus decode visceral and somatic pain. Neuron 2024; 112(22): 3734–3749.e5.

94.

Kang

Hua

Zhang

. Involvement of dopamine system in the regulation of the brain corticotropin-releasing hormone in paraventricular nucleus in a rat model of chronic visceral pain. Neurol Res 2018; 40: 650–657.

95.

Song

Meng

Hua

Song

Qin

Cao

Zhang

. Disinhibition of PVN-projecting GABAergic neurons in AV region in BNST participates in visceral hypersensitivity in rats. Psychoneuroendocrinology 2020; 117: 104690.

96.

Huang

Song

Liu

Luo

Yin

Zhang

. BNST_AV^GABA-PVN^CRF circuit regulates visceral hypersensitivity induced by maternal separation in Vgat-Cre mice. Front Pharmacol 2021; 12: 615202.

97.

Huang

Guo

Shao

Hua

Zhang

. Glutamatergic and GABAergic anteroventral BNST projections to PVN CRH neurons regulate maternal separation-induced visceral pain. Neuropsychopharmacology 2023; 48: 1778–1788.

98.

Zhu

Huang

. Upregulation of KDM6B in the anterior cingulate cortex contributes to neonatal maternal deprivation-induced chronic visceral pain in mice. Mol Pain 2024; 20: 17448069241260349.

99.

Tian

Zhang

Wang

. Overexpression of GRK6 alleviates chronic visceral hypersensitivity through downregulation of P2Y6 receptors in anterior cingulate cortex of rats with prenatal maternal stress. CNS Neurosci Ther 2022; 28: 851–861.

100.

Zhang

. Identification of a glutamatergic claustrum-anterior cingulate cortex circuit for visceral pain processing. J Neurosci 2022; 42: 8154–8168.

101.

Wang

Zhang

Cao

Liu

. Facilitation of synaptic transmission in the anterior cingulate cortex in viscerally hypersensitive rats. Cereb Cortex 2015; 25: 859–868.

102.

Ren

Qiu

Wan

Fan

Zhang

Chen

Bai

. Anterior cingulate cortex mediates hyperalgesia and anxiety induced by chronic pancreatitis in rats. Neurosci Bull 2022; 38: 342–358.

103.

Mayer

Gupta

Kilpatrick

Hong

. Imaging brain mechanisms in chronic visceral pain. Pain 2015; 156(Suppl. 1): S50–S63.

104.

Dong

Zhan

Sun

Wang

Duan

Zhang

Chen

Huang

. Astrocytic ERK/STAT1 Signaling contributes to maintenance of stress-related visceral hypersensitivity in rats. J Pain 2022; 23: 1973–1988.

105.

Peng

Zhang

Cao

Zhao

Gao

. Anterior cingulate cortex contributes to the hyperlocomotion under nitrogen narcosis. Neurosci Bull. Epub ahead of print 19 August 2024. DOI: 10.1007/s12264-024-01278-z.

106.

Song

Wei

Jiang

Dong

Zheng

Wang

Gao

Sun

Duan

Chen

Wang

Huo

Yao

Jing

Liu

Yang

Zhao

Wang

Cheng

Qin

Chen

Zhou

Chai

Kang

Wei

Wang

. An ACC-VTA-ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences. Nat Neurosci 2024; 27: 272–285.

107.

Ntamati

Acuna

Nevian

. Pain-induced adaptations in the claustro-cingulate pathway. Cell Rep 2023; 42: 112506.

108.

Zhang

Wei

Weng

. Paraventricular thalamus-insular cortex circuit mediates colorectal visceral pain induced by neonatal colonic inflammation in mice. CNS Neurosci Ther 2024; 30: e14534.

109.

Jurik

Auffenberg

Klein

Deussing

Schmid

Wotjak

Thoeringer

. Roles of prefrontal cortex and paraventricular thalamus in affective and mechanical components of visceral nociception. Pain 2015; 156: 2479–2491.

110.

Nalamachu

. An overview of pain management: the clinical efficacy and value of treatment. Am J Manag Care 2013; 19: s261–s266.

111.

Staahl

Dimcevski

Andersen

Thorsgaard

Christrup

Arendt-Nielsen

Drewes

. Differential effect of opioids in patients with chronic pancreatitis: an experimental pain study. Scand J Gastroenterol 2007; 42: 383–390.

112.

Delvaux

Beck

Jacob

Bouzamondo

Weber

Frexinos

. Effect of asimadoline, a kappa opioid agonist, on pain induced by colonic distension in patients with irritable bowel syndrome. Aliment Pharmacol Ther 2004; 20: 237–246.

113.

Brierley

Greenwood-Van Meerveld

Sarnelli

Sharkey

Storr

Tack

. Targeting the endocannabinoid system for the treatment of abdominal pain in irritable bowel syndrome. Nat Rev Gastroenterol Hepatol 2023; 20: 5–25.

114.

Camilleri

Boeckxstaens

. Dietary and pharmacological treatment of abdominal pain in IBS. Gut 2017; 66: 966–974.

115.

Yin

Han

Liu

Dong

Duan

Huo

Sun

Cheng

. Targeting peripheral µ-opioid Receptors or mu-opioid receptor-expressing neurons does not prevent morphine-induced mechanical allodynia and anti-allodynic tolerance. Neurosci Bull 2023; 39: 1210–1228.

116.

Bouwense

de Vries

Schreuder

Olesen

Frokjaer

Drewes

van Goor

Wilder-Smith

. Systematic mechanism-orientated approach to chronic pancreatitis pain. World J Gastroenterol 2015; 21: 47–59.

117.

Coelho

Fitzgerald

Lee

Winchester

Dinan

Cryan

. The effects of gabapentin in two animal models of co-morbid anxiety and visceral hypersensitivity. Eur J Pharmacol 2011; 667: 169–174.

118.

Zhang

Liu

Chen

Koga

Zhang

Zhuo

. Effects of NB001 and gabapentin on irritable bowel syndrome-induced behavioral anxiety and spontaneous pain. Mol Brain 2014; 7: 47.

119.

Chen

Mao

. Update on neuropathic pain treatment: ion channel blockers and gabapentinoids. Curr Pain Headache Rep 2013; 17: 359.

120.

Olesen

Graversen

Bouwense

van Goor

Wilder-Smith

Drewes

. Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis. PLoS One 2013; 8: e57963.

121.

Lee

Hong

Cui

Sharma

Lee

Choi

. Transient receptor potential vanilloid type 1 antagonists: a patent review (2011 - 2014). Expert Opin Ther Pat 2015; 25: 291–318.

122.

Winston

Shenoy

Yin

Pendyala

Pasricha

. Transient receptor potential vanilloid 1 mediates hyperalgesia and is up-regulated in rats with chronic pancreatitis. Gastroenterology 2007; 133: 1282–1292.

123.

Lapointe

Basso

Iftinca

Flynn

Chapman

Dietrich

Vergnolle

Altier

. TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis. Am J Physiol Gastrointest Liver Physiol 2015; 309: G87–G99.

124.

Chey

Lembo

Lavins

Shiff

Kurtz

Currie

MacDougall

Jia

Shao

Fitch

Baird

Schneier

Johnston

. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol 2012; 107: 1702–1712.

125.

Castro

Harrington

Hughes

Martin

Shea

Jin

Jacobson

Hannig

Mann

Cohen

MacDougall

Lavins

Kurtz

Silos-Santiago

Johnston

Currie

Blackshaw

Brierley

. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate. Gastroenterology 2013; 145: 1334–1346.e1–e11.

126.

Honore

Mikusa

Bianchi

McDonald

Cartmell

Faltynek

Jarvis

. TNP-ATP, a potent P2X3 receptor antagonist, blocks acetic acid-induced abdominal constriction in mice: comparison with reference analgesics. Pain 2002; 96: 99–105.

127.

Shenoy

Winston

Mittal

Pasricha

. P2X receptor-mediated visceral hyperalgesia in a rat model of chronic visceral hypersensitivity. Gut 2008; 57: 1230–1237.

128.

Fregni

Freedman

Pascual-Leone

. Recent advances in the treatment of chronic pain with non-invasive brain stimulation techniques. Lancet Neurol 2007; 6: 188–191.

129.

Tsubokawa

Katayama

Yamamoto

Hirayama

Koyama

. Chronic motor cortex stimulation in patients with thalamic pain. J Neurosurg 1993; 78: 393–401.

130.

Fregni

Potvin

Dasilva

Wang

Lenkinski

Freedman

Pascual-Leone

. Clinical effects and brain metabolic correlates in non-invasive cortical neuromodulation for visceral pain. Eur J Pain 2011; 15: 53–60.

131.

Zhao

Zhu

Zheng

Peng

Yang

Yuan

Chen

. Deep transcranial magnetic stimulation as a potential approach for digital pain management in patients with psychotic disorder. Neurosci Bull 2023; 39: 89–93.

132.

Ibrahim

Abdelhameed

Kamal

SMM

Khedr

EMH

Kotb

HIM

. Effect of transcranial direct current stimulation of the motor cortex on visceral pain in patients with hepatocellular carcinoma. Pain Med 2018; 19: 550–560.

133.

Algladi

Harris

Whorwell

Paine

Hamdy

. Modulation of human visceral sensitivity by noninvasive magnetoelectrical neural stimulation in health and irritable bowel syndrome. Pain 2015; 156: 1348–1356.

134.

Scialpi

Cagini

Pierotti

De Santis

Pusiol

Piscioli

Magli

D’Andrea

Brunese

Rotondo

. Detection of small (≤ 2 cm) pancreatic adenocarcinoma and surrounding parenchyma: correlations between enhancement patterns at triphasic MDCT and histologic features. BMC Gastroenterol 2014; 14: 16.

135.

Splittgerber

Suwelack

Kadish

Moliadze

. The effects of 1 mA tACS and tRNS on children/adolescents and adults: investigating age and sensitivity to Sham stimulation. Neural Plast 2020; 2020: 8896423.

136.

Zhou

Wang

Mao

Zhang

Liu

Yang

Hayashi

Zhao

Chen

Liu

Tao

Zhang

. Sound induces analgesia through corticothalamic circuits. Science 2022; 377: 198–204.

137.

Villanueva

Dominguez-Munoz

Mearin

. Update in the therapeutic management of irritable bowel syndrome. Dig Dis 2001; 19: 244–250.

138.

Catanzaro

Occhipinti

Calabrese

Anzalone

Milazzo

Italia

Marotta

. Irritable bowel syndrome: new findings in pathophysiological and therapeutic field. Minerva Gastroenterol Dietol 2014; 60: 151–163.

139.

Camilleri

. Management options for irritable bowel syndrome. Mayo Clin Proc 2018; 93: 1858–1872.

140.

De Palma

Reed

Bercik

. Diet-microbial cross-talk underlying increased visceral perception. Gut Microbes 2023; 15: 2166780.

141.

Bellono

Bayrer

Leitch

Castro

Zhang

O’Donnell

Brierley

Ingraham

Julius

. Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell 2017; 170: 185–198.e16.

142.

Racke

Schworer

. Characterization of the role of calcium and sodium channels in the stimulus secretion coupling of 5-hydroxytryptamine release from porcine enterochromaffin cells. Naunyn Schmiedebergs Arch Pharmacol 1993; 347: 1–8.

Advances in the pathological mechanisms and clinical treatments of chronic visceral pain

Abstract

Keywords

Introduction

Ion channels in chronic visceral pain

Epigenetics related to chronic visceral pain

Neural circuits related to chronic visceral pain

Analgesics associated with chronic visceral pain

Non-opioid analgesics

Opioid analgesics

Adjunctive analgesics

Unconventional drug therapies

Non-invasive brain stimulation in chronic visceral pain

Conclusions

Footnotes

Author contribution

Declaration of conflicting interests

Funding

ORCID iDs

References