Chun Lin

Background: Paclitaxel produces a chronic, glove‐stocking neuropathy that is frequently accompanied by anxiety and depression. However, the neural circuits and molecular signals driving this pain–affect comorbidity remain unclear. Methods: Chemotherapy‐induced neuropathic pain (CINP) was established by paclitaxel injections in male rats. Mechanical and thermal sensitivity and negative emotional behaviors were assessed using behavioral tests. Parabrachial nucleus (PBN)–central amygdala (CeA) projections were traced with viral vectors, and optogenetics was used to manipulate PBN terminals. Prodynorphin (PDYN) and κ‐opioid receptor (KOR) mRNA levels were quantified by reverse transcription quantitative polymerase chain reaction (RT‐qPCR). Results: CINP rats developed persistent pain hypersensitivity and negative emotional behaviors, accompanied by increased CeA c‐Fos and PDYN expression without changes in KOR mRNA. Intra‐CeA administration of the KOR antagonist Navacaprant alleviated both pain and negative emotional behaviors. Optogenetic inhibition of the PBN–CeA pathway reduced CeA activation, attenuated pain hypersensitivity, and improved negative emotional behaviors, whereas pathway activation elicited both changes in naïve rats. Chronic inhibition of this pathway lowered CeA PDYN mRNA levels in CINP rats. Conclusion: The PBN‐CeA pathway contributes to paclitaxel‐induced neuropathic pain and anxiety‐like behavior, and is associated with increased dynorphin expression in the CeA. Targeting this pathway or its downstream KOR may provide a therapeutic strategy for chemotherapy‐related sensory and affective disturbances.

This study investigated the differential roles of Locus Coeruleus-Infralimbic cortex (LC-IL) and Locus Coeruleus-Prelimbic cortex (LC-PL) circuits in comorbid mechanical hyperalgesia and anxiety-like emotions in male rats with chronic post-surgical pain (CPSP). A total of 100 adult male Sprague-Dawley rats were randomly divided into 10 groups (n=10/group). Group included LC activation (sham+ChR2, sham+mch), LC–IL inhibition/activation (CPSP+NpHR, CPSP+mch; sham+ChR2, sham+mch), and LC–PL inhibition/activation (CPSP+NpHR, CPSP+mch; sham+ChR2, sham+mch). Using the skin/muscle incision and retraction procedure to establish CPSP or sham surgery. Optogenetic viruses (ChR2 for activation, NpHR for inhibition) or control virus (mCherry) were injected into the LC, with optical fibers implanted in the LC, IL, or PL. After 4 weeks of viral expression, blue or yellow light stimulation was applied. Mechanical paw withdrawal threshold was measured by Von-Frey filaments. Anxiety-like emotions was assessed by open field test and elevated plus maze. Blue light irradiation of the LC region and LC-IL neural circuit both induced mechanical hyperalgesia and anxiety-like emotions in the rats. Yellow light irradiation of the LC-IL neural circuit alleviated mechanical hyperalgesia and anxiety-like emotions in CPSP model rats. Blue or yellow light irradiation of the LC-PL neural circuit had no significant effect on mechanical hyperalgesia or anxiety-like emotions in the rats. The LC-IL circuit specifically regulates comorbid mechanical hyperalgesia and anxiety-like emotions in male CPSP rats, while the LC-PL circuit does not. These findings identify a sex-specific circuit mechanism and a potential therapeutic target for CPSP.

Visceral hypersensitivity is a hallmark feature of irritable bowel syndrome (IBS), yet its underlying mechanisms remain incompletely understood. In the present study, we found that miRNA-let7b5p was downregulated in the spinal cord of IBS model rats induced by neonatal colorectal distension. Concurrently, microglia exhibited a shift toward a pro-inflammatory M1 phenotype and selectively engulfed inhibitory synapses, resulting in impaired GABAergic neuronal function and disruption of the excitatory/inhibitory balance. Intrathecal administration of a miRNA-let7b5p agomir suppressed M1-type microglial activation in the spinal cord, reduced pro-inflammatory cytokine levels, and alleviated visceral hypersensitivity, whereas antagomir treatment induced visceral hypersensitivity in control rats. Mechanistically, MAP3K3 was identified as a direct target of miRNA-let7b5p, and its knockdown recapitulated the protective effects conferred by miRNA upregulation. Collectively, these findings demonstrate that miRNA-let7b5p attenuates IBS-associated visceral hypersensitivity by downregulating MAP3K3, thereby inhibiting spinal microglial activation and restoring GABAergic neuronal function. This study provides novel insights into the pathogenesis of IBS-related visceral hypersensitivity and highlights a potential therapeutic target for drug development.

Irritable bowel syndrome (IBS) is characterized by chronic visceral pain and anxiety comorbidity, yet the central mechanisms linking gut signals to persistent pain–emotion dysregulation remain unclear. This study investigated whether hippocampal Lipocalin-2 (LCN2) drives neuronal ferroptosis to mediate visceral hypersensitivity and anxiety-like behaviors in a neonatal rat IBS model. Using a colorectal distension model, we conducted behavioral tests, molecular assays, and electron microscopy. IBS-like rats exhibited upregulated hippocampal LCN2 expression, predominantly in neurons, alongside ferroptosis hallmarks including increased ACSL4, decreased GPX4, elevated Fe²⁺ and MDA levels, and mitochondrial damage. Inhibition of ferroptosis reversed visceral pain and anxiety-like behaviors. LCN2 knockdown in the hippocampal CA1 region alleviated IBS-related phenotypes, while LCN2 overexpression in normal rats induced similar behavioral and ferroptotic changes. These findings identify a novel LCN2–ferroptosis axis in hippocampal neurons that critically mediates gut–brain dysregulation in IBS. Our study provides the first causal evidence linking LCN2-driven ferroptosis to visceral pain–anxiety comorbidity, offering new mechanistic insights and potential therapeutic targets for IBS and related gut–brain disorders.

Introduction: Irritable bowel syndrome (IBS) is a prevalent chronic functional gastrointestinal disorder characterized by visceral hypersensitivity (VH), affecting over 10% of the global population. Current treatments for IBS have notable limitations, highlighting the need for novel therapeutic strategies to address chronic visceral pain and associated comorbidities. Objectives: This study aimed to investigate whether bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) can alleviate chronic visceral pain in IBS and to explore the underlying molecular mechanisms, with a specific focus on the Nrf-2/HO-1 oxidative stress pathway. Methods: High-quality BMSC-Exos were isolated and characterized. In vitro, their neuroprotective effects were assessed in oxidatively stressed neurons. In vivo, IBS model rats received intrathecal injections of BMSC-Exos, and their effects on visceral pain sensitivity and anxiety-like behaviors were evaluated. Spinal cord tissues were analyzed to determine modulation of the Nrf-2/HO-1 pathway. Results: In vitro studies demonstrated that BMSC-Exos effectively rescued oxidative stress-induced neuronal damage. In IBS rats, intrathecally administered BMSC-Exos were internalized by spinal cord neurons, significantly reducing visceral hypersensitivity and anxiety-like behaviors. Mechanistically, BMSC-Exos upregulated the Nrf-2/HO-1 antioxidant pathway, mitigating oxidative stress-induced neuronal damage. Conclusion: These findings demonstrate that BMSC-Exos alleviate chronic visceral pain and comorbid anxiety in IBS rats, likely through Nrf-2/HO-1-mediated oxidative stress reduction in spinal neurons. These results highlight BMSC-Exos as a promising acellular therapeutic strategy for IBS, offering potential applications for this debilitating disorder.

Irritable bowel syndrome (IBS) is characterized by chronic visceral pain, but its molecular mechanisms remain controversial, hindering effective treatment. This research is to investigate the role of lncRNA RT1-CE10 in chronic visceral pain associated with IBS and to elucidate the underlying molecular mechanisms. An IBS rat model was developed in rats, and RNA-Seq analysis was conducted to assess lncRNA RT1-CE10 expression. The subcellular localization of lncRNA RT1-CE10 and its co-localization with ATP1a3 in spinal cord neurons were examined. AAV was used to over-express lncRNA RT1-CE10 in the spinal cord to study its effects on ATP1a3 levels and pain response, with knockdown experiments to evaluate the impact of reduced lncRNA RT1-CE10. The RNA-Seq analysis revealed a significant down-regulation of lncRNA RT1-CE10 in IBS rats. The lncRNA was found to be expressed in both the cytoplasm and the nucleus and to co-localize with ATP1a3 in spinal cord neurons. Over- expression of lncRNA RT1-CE10 via AAV-lncRT1-CE10 increased ATP1a3 levels and alleviated visceral pain response, while knockdown of lncRNA RT1-CE10 decreased ATP1a3 levels and enhanced visceral pain response. Additionally, a marked decrease in ATP1a3 expression was observed in the spinal cords of IBS rats. Modulating ATP1a3 expression either through over-expression or knockdown could alleviate or aggravate chronic visceral pain, respectively. LncRNA RT1-CE10, which is lowly expressed in the spinal cord of IBS rats, interacts with ATP1a3 and influences chronic visceral pain. These findings could lead to the development of targeted therapeutic interventions for IBS.

Accumulating evidences suggest dysfunctions in the hippocampus are associated with chronic pain. Nevertheless, the role of hippocampal circuitry in pain memories and emotional responses is not yet fully understood. In this study, we utilized a comprehensive approach that combined electromyography (EMG), photochemical genetic techniques, and anxiety‐related behavioral paradigms to investigate the involvement of dorsal hippocampus (DH) and ventral hippocampus (VH) in visceral sensitivity and anxiety behaviors in male rats. Our results demonstrated that IBS‐like rats exhibited comorbid visceral hypersensitivity and anxiety, along with the number of activated neurons in the VH was higher than that in the DH. Manipulation of glutamatergic neurons in the hippocampus was identified as a crucial mechanism underlying the mediation of both visceral sensitivity and anxiety behaviors. Specifically, optogenetic activation of the DH induced both visceral hypersensitivity and anxiety, while activation of the VH induced anxiety but did not affect visceral sensitivity. Conversely, chemogenetic inhibition of the DH reduced both visceral hypersensitivity and anxiety, whereas inhibition of the VH alleviated anxiety but did not alleviate visceral hypersensitivity in IBS‐like rats. Our study highlights the important role of early life stress in inducing visceral hypersensitivity and anxiety, and further elucidates the distinct functional contributions of the DH and VH to these behavioral changes. These findings provide a theoretical basis for the diagnosis and treatment of IBS, and suggest that targeting specific hippocampal neuron subtypes may represent a promising therapeutic approach.

Background: Irritable bowel syndrome (IBS) is one of the typical representatives of chronic functional visceral pain that lacks effective treatment. Recently, attention has been given to the role of microglia in IBS, particularly the activation of spinal microglia and the subsequent release of Cathepsin S (Cat S), a proteolytic enzyme. However, the specific role of spinal Cat S in IBS remains to be elucidated. The purpose of this study is to investigate the mechanisms underlying the regulation of visceral hypersensitivity in IBS-like rats by Cat S. Methods: An IBS-like rat model was developed, and visceral sensitivity was tested via the electromyographic (EMG) response to colorectal distention (CRD) and pain threshold. Western blot and immunofluorescence were used to examine the expressions of proteins. The effects of inhibitors or neutralizing antibodies on visceral pain and the downstream molecular expressions were detected. The open-field test was performed to evaluate locomotor activity and anxiety-like behaviors in rats. Results: We discovered that spinal Cat S was upregulated and colocalized with microglia in IBS-like rats. Treatment with LY3000328, a selective inhibitor of Cat S, dose-dependently down-regulated EMG amplitude and Fractalkine (FKN) expression, indicating that Cat S regulated visceral hypersensitivity via activating FKN in IBS-like rats. Furthermore, the expressions of FKN, CX3CR1, and p-p38 MAPK were elevated in IBS-like rats whereas inhibition of these molecules could alleviate visceral pain. Moreover, pharmacological inhibitor experiments suggested the activation of CX3CR1 by FKN facilitated p38 MAPK phosphorylation, which in turn promoted Cat S expression in IBS-like rats. Conclusions: Neonatal adverse stimulation might enhance the expression of spinal microglial Cat S, thereby activating the FKN/CX3CR1/p38 MAPK pathway and lead to visceral hypersensitivity in IBS-like rats. As a selective inhibitor of Cat S, LY3000328 could become a potential therapeutic option for IBS.

Background: Visceral pain is a complex and heterogeneous disorder that is considered more prominent compared to somatic pain, due to its multiple and complex causes and accompanying emotional and mood disorders. Research has become increasingly extensive over the years, but a bibliometric analysis of this field is lacking. The aim of this study was to analyze global research trends in visceral pain over the past 40 years through visual analysis.Methods: We conducted a comprehensive search of the literature from January 1981 to December 2021 using the Web of Science core database. The medical subject term ‘visceral pain’ was searched. We used CiteSpace and VOSviewer for bibliometric analysis and network visualization, including top-ranked authors, keywords, research collaborations, and literature co-occurrence network analysis.Results: A total of 5,047 articles were included in the analysis. The number of articles on visceral pain has continued to grow steadily over the past 40 years. The United States (1,716 articles), University of California (159 articles), and Neurogastroenterology and Motility (276 articles) were the country, institution, and journal with the most publications, respectively. Keyword analysis showed that inflammation, visceral hypersensitivity, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), anxiety, and quality of life were the research trends and priorities in this research field.Conclusion: Visceral pain-related research has received increasing attention in recent decades. However, there are still many unresolved issues in the field of visceral pain, such as the specific molecular mechanisms and clinical treatments between visceral pain and inflammation, IBD, IBS, anxiety, and quality of life, which may require further exploration based on modern scientific and technological means and more basic research, especially for the therapeutic targets of visceral pain, which may become a hot spot for future research and provide guidance for the treatment of clinical diseases related to visceral pain.