Molecular Pain最新文献

{"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}

{"title":"Risk factors associated with chronic pain and fibromyalgia-like symptoms post-COVID hospitalization.","authors":"Linamara Rizzo Battistella, Marta Imamura, Xinyi Christine Zhang, Kevin Pacheco-Barrios, Felipe Fregni","doi":"10.1177/17448069251369069","DOIUrl":"10.1177/17448069251369069","url":null,"abstract":"<p><p>Post-COVID syndrome (PCS) may manifest as chronic pain and fibromyalgia-like symptoms, but the specific risk factors contributing to these outcomes remain poorly understood. We conducted a prospective cohort study using data from the ongoing \"Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)\" study to identify predictors of chronic pain and fibromyalgia-related phenotypes among previously hospitalized COVID-19 patients. Participants were adults (<i>n</i> = 756, mean age 55, 47% female) hospitalized between March and August 2020 at the University of São Paulo Medical School. Clinical and demographic data from hospitalization, along with psychological, functional, and cognitive assessments at 3-11 months post-discharge (phase 1), were used to predict chronic pain, chronic widespread pain (CWP), fibromyalgia-like symptoms (FLS), and probable fibromyalgia (FM) at a 2-3 year follow-up (phase 2). Multivariate logistic regression analyses revealed that higher anxiety/depression severity (OR 1.35; 95% CI 1.09-1.69; <i>p</i> = 0.008) and reduced left handgrip strength (OR 0.95; 95% CI 0.92-0.98; <i>p</i> < 0.001) at phase 1 significantly predicted chronic pain at phase 2. For fibromyalgia-related phenotypes, greater left-side pain, insomnia severity, and weaker left handgrip strength were consistently associated with increased risk across all outcomes (CWP, FLS, FM), with statistically significant odds ratios ranging from 1.07 to 1.44. These findings highlight key modifiable risk factors - particularly psychological distress, sleep disruption, and muscle weakness - that may contribute to the development of chronic pain and fibromyalgia symptoms following COVID-19 hospitalization. Early identification and targeted intervention on these domains could improve long-term outcomes in PCS populations.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251369069"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799724","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":"Meningeal macrophages mask incision pain sensitization in male rats.","authors":"Mahshad Kolahdouzan, Shahrzad Ghazisaeidi, YuShan Tu, Milind M Muley, Eder Gambeta, Michael W Salter","doi":"10.1177/17448069251383593","DOIUrl":"10.1177/17448069251383593","url":null,"abstract":"<p><strong>Introduction: </strong>Meninges surrounding the brain and spinal cord house a variety of immune cell types including macrophages that express the CD206 mannose receptor. Here, we investigated whether CD206⁺ macrophages in the meninges play a role in regulating nociception and pain hypersensitivity.</p><p><strong>Methods: </strong>We selectively depleted CD206⁺ macrophages in the meninges around the lumbar spinal cord by intrathecal administration of anti-CD206 coupled to saporin, and determined the effects of CD206⁺ macrophage depletion on responses in naïve rats and in those that had received a skin incision to the upper hindlimb. In addition, we used RNAseq to investigate transcriptional changes in lumbar meninges and dorsal root ganglia. Experiments were done in both male and female rats.</p><p><strong>Results: </strong>Depleting CD206⁺ meningeal macrophages did not alter basal responses in naïve animals of either sex. By contrast depleting these cells after skin injury induced mechanical hypersensitivity in male rats, without changes in thermal sensitivity but had no effect in females. In male rats with skin incision injury, we found that the mechanical hypersensitivity induced by depleting CD206⁺ meningeal macrophages was reversed by administering the NMDAR antagonist, APV. In addition, the hypersensitivity was reversed by an enhancer of KCC2 function, CLP290. Unexpectedly, skin incision caused significant transcriptional changes in the meninges, but only in male rats.</p><p><strong>Conclusions: </strong>Taken together, our results indicate that while CD206⁺ meningeal macrophages do not regulate basal nociception in naïve rats, after skin incision injury, these cells mask mechanical hypersensitivity in male rats only. Thus, we conclude that in a sex-dependent manner CD206⁺ meningeal macrophages prevent the spread of pain hypersensitivity after a minor injury. Importantly, the skin incision we used was comparable to that used in \"sham\" controls in numerous rodent studies of neuropathic pain. Our findings have, therefore, potentially broad implications for re-interpreting results from previous neuropathic pain research.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251383593"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12559685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075756","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":"Cooling from noxious heat to normal skin temperatures excites a subpopulation of cutaneous Aβ-fiber low-threshold mechanoreceptors.","authors":"Akihiro Yamada, Ayaka I Yamada, Jennifer Ling, Jianguo G Gu","doi":"10.1177/17448069251359843","DOIUrl":"10.1177/17448069251359843","url":null,"abstract":"<p><p>Sensing cooling temperatures is achieved by primary afferent endings located in the skin and is essential for the survival of animals. TRPM8 channels, primarily expressed in cutaneous C-fibers, have been established as receptors for cooling temperatures, sensing innocuous cooling from the normal skin temperature near 30°C to 17°C, and noxious cooling below 17°C. A cooling sensation is also felt when skin temperatures are first elevated to higher temperatures, for example, noxious heat, and then cool down to the normal skin temperature near 30°C. It is currently not clear what types of cutaneous afferent fibers are involved in sensing the cooling from a high heat to the normal skin temperature. Cutaneous Aβ-fiber low-threshold mechanoreceptors (Aβ-LTMRs) are primarily involved in the sense of touch and are thought to play no role in cooling sensation. In the present study, we conducted the opto-electrophysiological recordings from the skin-nerve preparations made from the hindpaw glabrous skin of Nav1.8-ChR2 transgenic mice. In these transgenic mice, Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors are primarily Aβ-LTMRs, and Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors are mainly high-threshold mechanoreceptors (Aβ-HTMRs). Neither Aβ-LTMRs nor Aβ-HTMRs responded to temperature rising from 30°C to the noxious heat of 43°C. However, a subpopulation of Aβ-LTMRs, but not Aβ-HTMRs, robustly fires action potential impulses in response to the temperature drop from 43°C to 30°C. This finding reveals for the first time that a subpopulation of Aβ-LTMRs senses the cooling for a temperature drop from noxious heat to normal skin temperature.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251359843"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567553","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":"The peripheral PI3K/AKT/MLC signalling pathway alleviates myofascial pain in rats by inhibiting abnormal contraction at myofascial trigger points.","authors":"Mingyang Zhang, Yuchang Zhu, Feihong Jin, Yu Liu, Luhua Yin","doi":"10.1177/17448069251376205","DOIUrl":"10.1177/17448069251376205","url":null,"abstract":"<p><strong>Background: </strong>Myofascial trigger points (MTrPs) for abnormal skeletal muscle contraction are the cause of myofascial pain. The G protein-coupled receptor family and tyrosine kinase receptor family regulate the contraction of vascular smooth muscle through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Phosphorylated myosin light chain (p-MLC) is associated with skeletal muscle contraction. The aim of the current study was to explore the effect and mechanism of the PI3K/AKT/MLC signalling pathway on myofascial pain in rats.</p><p><strong>Methods: </strong>A rat model of myofascial pain was established by a blunt strike to the gastrocnemius muscle combined with centrifugal exercise for 8 weeks, followed by recovery for 4 weeks. Different concentrations of the PI3K inhibitor LY294002 (0.01, 0.1, or 1 mg/ml) were subsequently injected into the MTrPs of rats with myofascial pain to observe the effects on the mechanical tenderness threshold at the MTrPs.</p><p><strong>Results: </strong>LY294002 (0.1 mg/ml) inhibited myofascial pain at 0.5, 1 and 2 h after injection, and LY294002 (1 mg/ml) inhibited myofascial pain at 0.5, 1, 2 and 4 h after injection. The expression of PI3K increased on the enlarged muscle fibre membrane at MTrPs. LY294002 (1 mg/ml) inhibited the expression of PI3K, p-AKT, and p-MLC and the abnormal contraction of muscle fibres at MTrPs and alleviated nerve fibre compression at MTrPs. Moreover, LY294002 inhibited the expression of Fos in the spinal dorsal horn of rats with myofascial pain.</p><p><strong>Conclusions: </strong>These findings suggested that the increased expression of PI3K/p-AKT/p-MLC was related to myofascial pain in rats and that the PI3K inhibitor LY294002 might alleviate myofascial pain in rats by inhibiting abnormal contraction at MTrPs.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251376205"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12461083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962160","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":"Advanced cancer perineural invasion induces profound peripheral neuronal plasticity, pain, and somatosensory mechanical deactivation, unmitigated by the lack of TNFR1. Part. 1: Behavior and single-cell in vivo electrophysiology.","authors":"Silvia Gutierrez, Renee A Parker, Morgan Zhang, Maria Daniela Santi, Yi Ye, M Danilo Boada","doi":"10.1177/17448069251314738","DOIUrl":"10.1177/17448069251314738","url":null,"abstract":"<p><p>Patients with cancer perineural invasion (PNI) report greater spontaneous pain and mechanical allodynia. Here, we examine the impact of the disease on the peripheral sensory system, the excitability changes induced by PNI at the dorsal root ganglia, and the potential protective role of the absence of Tumor Necrosis Factor-α Receptor 1 (TNFR1). To study these effects, we use a murine model generated by injecting mouse oral cancer squamous cell carcinoma (MOC2) into the sciatic nerve (MOC2-PNI) in both male and female mice. We found that MOC2-PNI induces a profound change in the somatosensory landscape by deactivating/blocking the peripheral inputs while modulating the afferent's sensibility (tactile desensitization with concurrent nociceptive sensitization) and demyelination without inducing spontaneous activity. All these changes caused by MOC2-PNI are unmitigated by the absence of TNFR1. We conclude that MOC2-PNI induces an aberrant neuronal excitability state and triggers extreme gender-specific neuronal plasticity. These data allow us to speculate on the role of such plasticity as a powerful defense mechanism to prevent terminal sensory dysfunction, the rise of chronic pain, and extend animals' survivability.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251314738"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11898231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374456","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":"<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}

{"title":"Long-term effects on functional brain networks in adolescents treated for lumbar disc herniation.","authors":"Sebastian Blomé, Granit Kastrati, Sebastian Pontén, Martin Jonsjö, Tobias Lagerbäck, Mikael Skorpil, Hans Möller, Maria Lalouni, Peter Fransson, Paul Gerdhem, William Hedley Thompson, Karin Jensen","doi":"10.1177/17448069251376189","DOIUrl":"10.1177/17448069251376189","url":null,"abstract":"<p><p>Long-term effects of lumbar disc herniation treatment on brain function are poorly understood, and it is unclear when surgery should be recommended over non-operative treatment. The overall aim of the present study was to determine potential long-term effects on brain networks among individuals who received either surgical or non-operative treatment for lumbar disc herniation in adolescence. Brain network connectivity was assessed for individuals who received surgical treatment or non-operative treatment, and controls with no history of lumbar disc herniation. Prior to analysis, brain connectivity measures between groups were determined as main outcome, using functional magnetic resonance imaging. On average 12 years after treatment onset, the surgically treated cohort exhibited distinctly different functional brain connectivity, compared with both non-operative treatment and controls. The difference was neither attributed to self-reported pain, nor lumbar spine morphology. The findings suggest that surgical treatment for lumbar disc herniation in adolescence may be associated with a long-term imprint on the functional brain connectome.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"21 ","pages":"17448069251376189"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12536111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313365","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":"Exploring novel non-opioid pathways and therapeutics for pain modulation.","authors":"Isabella Alessi, Kaysie L Banton, Sliter J, Zaw-Mon C, Palacio Ch, Ryznar Rj, Bar-Or D","doi":"10.1177/17448069251327840","DOIUrl":"10.1177/17448069251327840","url":null,"abstract":"<p><p>The opioid crisis has highlighted the urgent need for alternative pain management strategies. This review explores novel non-opioid targets and pathways involved in pain modulation, highlighting advancements in understanding and therapeutic potential. Pain, a multifaceted phenomenon with nociceptive, neuropathic, and inflammatory components, involves intricate molecular signaling cascades. Key pathways reviewed include voltage-gated sodium channels (Nav1.7, Nav1.8, Nav1.9), inflammasome complexes (NLRP3), the kynurenine pathway, prostaglandins, and bradykinin-mediated signaling. Emerging therapeutics such as selective Nav channel blockers, NLRP3 inhibitors, kynurenine pathway modulators, EP receptor antagonists, and bradykinin receptor antagonists offer promising alternatives to opioids. Despite challenges in clinical translation, these developments signal a paradigm shift in pain management, with precision-focused therapies poised to address unmet needs. This review emphasizes the importance of integrating molecular insights into the development of safer, more effective analgesics, setting the stage for transformative advancements in non-opioid pain relief.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251327840"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605910","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}