Molecular PainPub Date : 2025-07-03DOI: 10.1177/17448069251358692
Ying Tang, Zihan Liu, Xianhe Wu, Zhengqing He, Fan Yang, Huiqin Chen, Yu Chen, Qibin Zheng, Yang Huang, Aiqin Chen, Chun Lin
{"title":"EXPRESS: The Involvement of Spinal lncRNA RT1-CE10 in Chronic Functional Visceral Pain.","authors":"Ying Tang, Zihan Liu, Xianhe Wu, Zhengqing He, Fan Yang, Huiqin Chen, Yu Chen, Qibin Zheng, Yang Huang, Aiqin Chen, Chun Lin","doi":"10.1177/17448069251358692","DOIUrl":"https://doi.org/10.1177/17448069251358692","url":null,"abstract":"<p><p>Irritable bowel syndrome (IBS) is characterised 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.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251358692"},"PeriodicalIF":2.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular PainPub Date : 2025-06-06DOI: 10.1177/17448069251351045
Jiaqi Dong, Jingyi Wei, Hongwei Tong, Xiaohua Shi, Menghui Yuan, Yiwei Cao, Mohammed A El-Magd, Qiang Chen, Hongxin Zhang, Peng Yuan, Jiao Mu
{"title":"EXPRESS: Circadian genes NPAS2 alleviate thermal nociceptive sensitization on CFA-induced inflammatory pain in mice.","authors":"Jiaqi Dong, Jingyi Wei, Hongwei Tong, Xiaohua Shi, Menghui Yuan, Yiwei Cao, Mohammed A El-Magd, Qiang Chen, Hongxin Zhang, Peng Yuan, Jiao Mu","doi":"10.1177/17448069251351045","DOIUrl":"https://doi.org/10.1177/17448069251351045","url":null,"abstract":"<p><p>Pain, particularly chronic pain, is a primary driver for patients seeking physical therapy. Inflammation is critically involved in both the pathogenesis and persistence of chronic pain. Neuronal PAS domain protein 2 (NPAS2), a core circadian transcriptional regulator, has been implicated in modulating pain-related stress responses. First, we investigated the expression of NPAS2 in nociceptive sensitized mice treated with CFA. Next, we systematically explored the effects of CFA on astrocyte and inflammatory factor release in NPAS2 knockout mice. The results showed that knockout of the NPAS2 gene did not affect the pain threshold of mice under normal physiological conditions, but reduced the mechanical and heat pain thresholds of 50% of CFA pedal-injected mice, resulting in nociceptive sensitization. It may be induced by promoting astrocyte activation and inducing cytokine (IL-1β, IL-6, TNF-α, NF-κB) expression. These findings suggest that NPAS2 could serve as both a prognostic biomarker for pain chronification and a novel therapeutic target for biologically tailored interventions.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251351045"},"PeriodicalIF":2.8,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular PainPub Date : 2025-05-07DOI: 10.1177/17448069251342409
Wenhui Ma, Allen Dickie, Erika Polgár, Mansi Yadav, Raphaelle Quillet, Maria Gutierrez-Mecinas, Andrew M Bell, Andrew Todd
{"title":"EXPRESS: Expression of Tacr1 and Gpr83 by spinal projection neurons.","authors":"Wenhui Ma, Allen Dickie, Erika Polgár, Mansi Yadav, Raphaelle Quillet, Maria Gutierrez-Mecinas, Andrew M Bell, Andrew Todd","doi":"10.1177/17448069251342409","DOIUrl":"https://doi.org/10.1177/17448069251342409","url":null,"abstract":"<p><p>Anterolateral system (ALS) projection neurons underlie perception of pain, itch and skin temperature. These cells are heterogeneous, and there have therefore been many attempts to define functional populations. A recent study identified two classes of ALS neuron in mouse superficial dorsal horn (SDH) based on expression of the G protein-coupled receptors Tacr1 or Gpr83. It was reported that cells expressing these receptors formed largely non-overlapping populations, and that ~60% of ALS cells in SDH expressed Tacr1. An additional finding was that while Tacr1- and Gpr83-expressing ALS cells projected to several brain nuclei, their axons did not reach the ventral posterolateral (VPL) thalamic nucleus, which is reciprocally connected to the primary somatosensory cortex. These results were surprising, because we had reported that ~90% of SDH ALS neurons in the mouse possess the neurokinin 1 receptor (NK1r), which is encoded by Tacr1, and in addition the VPL is thought to receive input from lamina I ALS cells. Here we use retrograde and anterograde labelling in Tacr1CreERT2 and Gpr83CreERT2 mice to reinvestigate the expression of the receptors by ALS neurons and to reassess their projection patterns. We find that ~90% of ALS neurons in SDH express Tacr1, with 40-50% expressing Gpr83. We also show that axons of both Tacr1- and Gpr83-expressing ALS neurons reach the VPL. These results suggest that ALS neurons in the SDH that express these GPCRs show considerable overlap, and that they are likely to contribute to the sensory-discriminative dimension of pain through their projections to VPL.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251342409"},"PeriodicalIF":2.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular PainPub Date : 2025-01-01Epub Date: 2025-03-28DOI: 10.1177/17448069251333928
Ting Zhang, Le Qi, Kai Sun, Xiang Huan, Hao Zhang, Liwei Wang
{"title":"PDCD4 inhibition alleviates neuropathic pain by regulating spinal autophagy and neuroinflammation.","authors":"Ting Zhang, Le Qi, Kai Sun, Xiang Huan, Hao Zhang, Liwei Wang","doi":"10.1177/17448069251333928","DOIUrl":"10.1177/17448069251333928","url":null,"abstract":"<p><p>Neuropathic pain is still a clinical challenge. Inflammatory responses and autophagy in the spinal cord are important mechanisms for the occurrence and maintain of neuropathic pain. PDCD4 is an important molecule that regulates inflammation and autophagy. However, the regulatory role of PDCD4 is unknown in pain modulation. In this study we found that the expression of PDCD4 in the spinal cord of CCI mice was increased. Inhibition of PDCD4 by intrathecal injection of adeno-associated virus alleviated neuropathic pain hypersensitivity and enhanced autophagy in CCI mice, and inhibited the activation of MAPKs, as well as the expression of inflammatory factors. Intrathecal injection of autophagy inhibitor 3-MA reversed PDCD4 inhibition induced pain relief and change of autophagy. Our results indicate that spinal cord inhibition of PDCD4 alleviates pain sensitization in neuropathic pain mice through MAPKs and autophagy, and PDCD4 may be developed into a therapeutic target of neuropathic pain treatment.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251333928"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular PainPub Date : 2025-01-01Epub Date: 2025-02-13DOI: 10.1177/17448069251323666
Silvia Gutierrez, Renee A Parker, Morgan Zhang, Maria Daniela Santi, Yi Ye, Mario Danilo Boada
{"title":"Advanced cancer perineural invasion induces profound peripheral neuronal plasticity, pain, and somatosensory mechanical deactivation, unmitigated by the lack of TNFR1. Part 2. Biophysics and gene expression.","authors":"Silvia Gutierrez, Renee A Parker, Morgan Zhang, Maria Daniela Santi, Yi Ye, Mario Danilo Boada","doi":"10.1177/17448069251323666","DOIUrl":"10.1177/17448069251323666","url":null,"abstract":"<p><p>Preclinical studies addressing the peripheral effects of cancer perineural invasion report severe neuronal availability and excitability changes. Oral cell squamous cell carcinoma perineural invasion (MOC2-PNI) shows similar effects, modulating the afferent's sensibility (tactile desensitization with concurrent nociceptive sensitization) and demyelination without inducing spontaneous activity (see Part 1.). The current study addresses the electrical status (normal or abnormal) of both active (low threshold mechano receptors (LT) and high threshold mechano receptors (HT)) and inactive (F-type and S-type) afferents. Concurrently, we have also evaluated changes in the genetic landscape that may help to understand the physiological dynamics behind MOC2-PNI-induced functional disruption of the peripheral sensory system. We have observed that the altered cell distribution and mechanical sensibility of the animal's somatosensory system cannot be explained by cellular electrical dysfunction or MOC2-PNI-induced apoptosis. Although PNI does modify the expression of several genes related to cellular hypersensitivity, these changes are insufficient to explain the MOC2-PNI-induced aberrant neuronal excitability state. Our results indicate that genetic markers provide limited information about the functional hyperexcitable state of the peripheral system. Importantly, our results also highlight the emerging role of plasma membrane Ca<sup>2+</sup>-ATPase activity (PMCA) in explaining several aspects of the observed gender-specific neuronal plasticity and the reported cellular distribution switch generated by MOC2-PNI.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251323666"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143409338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular PainPub Date : 2025-01-01DOI: 10.1177/17448069251320233
Yukito Sashide, Mamoru Takeda
{"title":"Gut microbiota-derived short-chain fatty acid suppresses the excitability of rat nociceptive secondary neurons via G-protein-coupled receptor 41 signaling.","authors":"Yukito Sashide, Mamoru Takeda","doi":"10.1177/17448069251320233","DOIUrl":"10.1177/17448069251320233","url":null,"abstract":"<p><p>Short-chain free fatty acids (SCFAs) are generated by gut microbiota through anaerobic fermentation of dietary fibers. Although gut microbiota-derived SCFAs modulate voltage-gated Ca<sup>2+</sup> channels via G-protein-coupled receptor 41 (GPR41) in isolated sympathetic ganglion neurons, the influence of SCFAs, specifically propionic acid (PA), on the excitability of nociceptive neurons under in vivo conditions has yet to be ascertained. In the current study we assessed whether systemic PA administration diminishes the excitability of nociceptive trigeminal spinal nucleus caudalis (SpVc) wide-dynamic range neurons responding to mechanical stimulation. Extracellular single-unit recordings from SpVc wide-dynamic range neurons were performed in anesthetized rats after mechanical stimulation of the orofacial region. PA significantly and reversibly inhibited the mean firing frequency of SpVc neurons in response to both non-noxious and noxious mechanical stimuli in a dose-dependent manner. Simultaneous administration of a GPR41 inhibitor abolished the PA-induced inhibited firing rate of SpVc neurons, indicating that systemic PA decreased the excitability of nociceptive secondary trigeminal neurons by activating GPR41 signaling-mediated inhibition of voltage-gated Ca<sup>2+</sup> channels in the central terminals of the SpVc. Modulation of trigeminal nociception by systemic SCFA administration indicates that gut microbiota-derived SCFAs could be effective analgesic agents for relieving trigeminal pain, creating a new therapeutic strategy for the management of trigeminal pain, including clinical pain.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251320233"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Identification of genetic variations in μ opioid receptor in cats.","authors":"Kazumasu Sasaki, Junko Hasegawa, Kazutaka Ikeda, Tatsuya Ishikawa, Shinya Kasai","doi":"10.1177/17448069251327805","DOIUrl":"10.1177/17448069251327805","url":null,"abstract":"<p><p>μ-opioid receptor (MOP) plays a critical role in mediating opioid analgesic effects. Genetic variations, particularly those in the MOP gene (<i>Oprm1</i>), significantly influence individual variations in opioid efficacy and side effects across species, highlighting the need for pharmacogenomic research in human and veterinary contexts. This study aimed to identify single-nucleotide variations (SNVs) within <i>Oprm1</i> in 100 cats of various breeds. <i>Oprm1</i> spans over 170 kb and consists of five exons that combine to yield three splice variants in the cat Ensembl database. Among these variants, <i>Oprm1-202</i> is an ortholog of the <i>MOR-1</i> transcript, which is the most abundant in humans and mice. <i>Oprm1-202</i> shares 92% and 87% coding sequences (CDS) and 96% and 94% amino acid sequence identity with human and mouse <i>MOR-1</i>, respectively. Phylogenetic trees were constructed from the CDS and amino acid sequences of nine species, including humans, cats, and mice. Both the CDS and amino acid sequences of MOP in cats showed phylogenetic development closer to that of primates than of rodents. Four SNVs were identified in the CDS of <i>Oprm1</i>. One SNV was located in exon 1 and the other three in exon 2 of <i>Oprm1</i>, all of which were synonymous substitutions. Although synonymous mutations generally have a limited functional impact, they may influence splicing and receptor expression. Further research is required to assess the effects of these SNVs on opioid efficacy, receptor expression, and analgesic responses across breeds, considering the potential breed-specific genetic factors in cat species.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251327805"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular PainPub Date : 2025-01-01DOI: 10.1177/17448069251321339
Hongchun Xiang, Yuye Lan, Liang Hu, Renjie Qin, Hongping Li, Tao Weng, Yan Zou, Yongmin Liu, Xuefei Hu, Wenqiang Ge, Hong Zhang, Hui-Lin Pan, Na-Na Yang, Wentao Liu, Guowei Cai, Man Li
{"title":"AMPK activation mitigates inflammatory pain by modulating STAT3 phosphorylation in inflamed tissue macrophages of adult male mice.","authors":"Hongchun Xiang, Yuye Lan, Liang Hu, Renjie Qin, Hongping Li, Tao Weng, Yan Zou, Yongmin Liu, Xuefei Hu, Wenqiang Ge, Hong Zhang, Hui-Lin Pan, Na-Na Yang, Wentao Liu, Guowei Cai, Man Li","doi":"10.1177/17448069251321339","DOIUrl":"10.1177/17448069251321339","url":null,"abstract":"<p><p>Inflammatory pain presents a significant clinical challenge. AMP-activated protein kinase (AMPK) is recognized for its capacity to alleviate inflammation by inhibiting transcription factors such as nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription (STAT). Our prior research demonstrated that AMPK reduces inflammatory pain by inhibiting NF-κB activation and interleukin-1 beta (IL-1β) expression. However, the role of AMPK in regulating reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) by modulating STAT3 phosphorylation in inflammatory pain remains inadequately understood. This study aims to investigate the role of AMPK in modulating STAT3 phosphorylation in the macrophages of inflamed tissues to mitigate inflammatory pain. A Complete Freund's Adjuvant (CFA)-induced inflammatory pain model was established by subcutaneous injection into the plantar surface of the left hindpaw of adult male mice. Behavioral tests of mechanical allodynia and thermal latency were used to determine nociceptive behavior. Immunoblotting quantified p-AMPK and iNOS expression levels. Nuclear translocation of p-STAT3(Ser727) and STAT3 in macrophages was assessed by western blot and immunofluorescence. ROS accumulation and mitochondrial damage in NR8383 macrophages were detected by flow cytometry. Lentivirus infection cells experiment was performed to transfect vectors encoding the STAT3 S727D mutants. Treatment with the AMPK activator AICAR alleviated CFA-induced inflammatory pain, enhanced AMPK phosphorylation, and reduced iNOS expression in inflamed skin tissues. AICAR effectively prevented STAT3 nuclear translocation while promoting the phosphorylation of STAT3 (Ser727) in the cytoplasm. In vitro studies with CFA-stimulated NR8383 macrophages revealed that AICAR increased STAT3(Ser727) phosphorylation, curtailed iNOS expression, and attenuated ROS accumulation and mitochondrial damage. Furthermore, the S727D mutation, which enhances STAT3 phosphorylation, replicated the protective effects of AICAR against CFA-induced oxidative stress and mitochondrial dysfunction. Our study shows that the AMPK acitvation downregulates iNOS expression by inhibiting the STAT3 nuclear translocation and promotes cytoplasmic STAT3(Ser727) phosphorylation, which reduces ROS expression and mitochondrial dysfunction, thereby alleviating inflammatory pain. These findings underscore the therapeutic potential of targeting AMPK and STAT3 pathways in inflammatory pain management.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251321339"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular PainPub Date : 2025-01-01Epub Date: 2025-03-11DOI: 10.1177/17448069251327824
Ravinder S Saini, Rayan Ibrahim H Binduhayyim, Mohamed Saheer Kuruniyan, Artak Heboyan
{"title":"<i>In silico</i> exploration of bioactive secondary metabolites with anesthetic effects on sodium channels Nav 1.7, 1.8, and 1.9 in painful human dental pulp.","authors":"Ravinder S Saini, Rayan Ibrahim H Binduhayyim, Mohamed Saheer Kuruniyan, Artak Heboyan","doi":"10.1177/17448069251327824","DOIUrl":"10.1177/17448069251327824","url":null,"abstract":"<p><strong>Aim: </strong>To investigate the efficacy of medicinal plant bioactive secondary metabolites as inhibitors of voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9) in managing painful states of dental pulps.</p><p><strong>Methodology: </strong>Molecular docking, ADME prediction, toxicity profiling, and pharmacophore modeling were used to assess the binding affinities, pharmacokinetic properties, toxicological profiles, and active pharmacophores of the selected bioactive compounds.</p><p><strong>Results: </strong>Three compounds (Sepaconitine, Lappaconitine, and Ranaconitine) showed binding affinities (ΔG = -8.95 kcal/mol, -7.77 kcal/mol, and -7.44 kcal/mol, respectively) with all three Nav1.7, Nav1.8, and Nav1.9 sodium channels. The sepaconitine amine group formed hydrophobic interactions with key residues. The Lappaconitine benzene ring contributed to hydrophobic interactions and hydrogen bond acceptor interactions. The hydrophobic interactions of the ranaconitine amine group play a critical role with specific residues on Nav1.8 and Nav1.9.</p><p><strong>Conclusion: </strong>The natural fusicoccane diterpenoid derivatives Sepaconitine, Lappaconitine, and Ranaconitine are potential lead compounds for the development of novel analgesics as selective antihyperalgesic drugs, which will provide a new dental pharmacological intervention for managing painful dental pulp conditions. Further experimental validation and clinical studies that confirm the efficacy and safety of these compounds will strengthen their applicability in dental practice.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251327824"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Unraveling the role of gut microbiota and plasma metabolites in fibromyalgia: Insights from Mendelian randomization and dietary interventions.","authors":"Mengqi Niu, Jing Li, Xiaoman Zhuang, Chenkai Yangyang, Yali Chen, Yingqian Zhang, Michael Maes","doi":"10.1177/17448069251332140","DOIUrl":"10.1177/17448069251332140","url":null,"abstract":"<p><p>Fibromyalgia (FM) is a complex disorder characterized by chronic pain, fatigue, and functional impairments, with unclear pathological mechanisms. Gut microbiota and plasma metabolites have been implicated in FM, but their causal relationships remain unexplored. This study aims to assess the causal relationships between gut microbiota, plasma metabolites, and FM using Mendelian randomization (MR) analysis and to explore potential mediating mechanisms. Public genome-wide association study data were analyzed using bidirectional MR. Associations between gut microbiota, plasma metabolites, and FM were evaluated, and multivariable MR identified mediating metabolites. Results were validated with inverse variance weighted, MR-Egger, and weighted median methods, with metabolic pathway enrichment analysis for further insights. MR identified protective associations between FM and four taxa (family <i>Enterobacteriaceae</i>, genus <i>Butyricicoccus</i>, genus <i>Coprococcus1</i>, and order <i>Enterobacteriales</i>) and risk associations with genus <i>Eggerthella</i> and genus <i>Ruminococcaceae UCG005</i>. Additionally, 82 plasma metabolites linked to pathways such as caffeine metabolism, α-linolenic acid metabolism, GLP-1, and incretin regulation were associated with FM. Mediation analysis revealed <i>Enterobacteriaceae</i> and <i>Enterobacteriales</i> influenced FM risk through 2,3-dihydroxypyridine and palmitoylcholine. Personalized dietary interventions, such as limiting caffeine intake, increasing omega-3 fatty acid consumption, adopting a low glycemic index diet, and reducing the intake of high-oxalate foods, may effectively alleviate FM-related symptoms by modulating metabolic pathways, reducing inflammation, and mitigating oxidative stress. This study highlights the intricate interactions between the gut microbiota and metabolic pathways, providing critical scientific evidence and actionable targets for clinical interventions, dietary management, and precision medicine approaches in FM treatment.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251332140"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}