Molecular Pain最新文献

{"title":"FK506 causes pain by upregulating Na_V1.7 channels in the spinal dorsal root ganglia of Na_V1.7-ChR2 mice.","authors":"Toyoaki Maruta, Seiji Shiraishi, Satoshi Kouroki, Mio Kurogi, Naoyuki Hirata","doi":"10.1177/17448069251414260","DOIUrl":"10.1177/17448069251414260","url":null,"abstract":"<p><p>Calcineurin inhibitors, including tacrolimus (FK506), are used as immunosuppressive agents and can cause unexplained calcineurin inhibitor-induced pain syndrome (CIPS). We investigated how FK506 affects the expression of <i>Na_V1.7</i>, a voltage-gated Na⁺ channel implicated in pain perception that is upregulated in dorsal root ganglion (DRG) neurons in several pain disorders. We generated a model of FK506-induced pain by administering FK506 to Na_V1.7-ChR2 mice, which exhibit light-responsive pain. To evaluate nociceptive responses, paw withdrawal threshold (PWT) was measured using the von Frey test. The optogenetic place aversion (OPA) and light irradiation paw withdrawal tests were also performed. On the 11th day of initial injection, DRGs were dissected from mice under anesthesia and analyzed for <i>Na_V1.7</i> expression using quantitative reverse transcription PCR (RT-qPCR). PWT was also measured for mice that received the selective Na_V1.7 inhibitor or vehicle. PWT was lower in FK506-treated mice than in those administered the vehicle on the 8th and 12th days after initial FK506 injection (<i>p</i> < 0.05). Mechanical hypersensitivity was reversible and peaked at around 10 days after FK506 administration. OPA and light irradiation paw withdrawal test results corroborated the hypersensitivity to light-responsivity. <i>Na_V1.7</i> mRNA levels in DRG were higher in FK506-treated mice than in those administered the vehicle on the 11th day (<i>p</i> < 0.05). A selective Na_V1.7 inhibitor reversed FK506-induced pain. Increased <i>Na_V1.7</i> expression in DRG neurons may be responsible for FK506-induced peripheral neuropathy. Our findings suggest that endogenous calcineurin regulates <i>Na_V1.7</i> expression. Thus, selective Na_V1.7 inhibition could be a potential therapeutic strategy for CIPS.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251414260"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12833204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892692","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":"Caffeic acid phenethyl ester attenuates inflammatory pain through promoting spinal microglial M1-to-M2 polarization by suppressing the PI3K/Akt/NF-κB pathway and attenuating peripheral inflammation.","authors":"Dongjie Wang, Yuhua Li, Chaobo Ni, Longsheng Xu, Xiaogeng Huang, Shuyao Zhang, Guofeng Shen, Heng Zhang, Huadong Ni, Ming Yao, Xuewu Lin, Gang Liu","doi":"10.1177/17448069251410746","DOIUrl":"10.1177/17448069251410746","url":null,"abstract":"<p><p>Inflammatory pain is a major global health challenge, significantly affecting quality of life and emotional well-being. Current treatment options are limited and often accompanied by adverse effects. Caffeic acid phenethyl ester (CAPE), a natural compound with notable anti-inflammatory properties, has not yet been fully elucidated for its efficacy in inflammatory pain. This work examined the role of CAPE in modulating inflammatory pain. Inflammatory pain was induced in mice by administration of Complete Freund's Adjuvant (CFA), and pain relief was assessed through mechanical and thermal sensitivity tests. Combined with network pharmacology and molecular docking analysis, the PI3K/Akt/NF-κB pathway was identified as a potential therapeutic target. Further validation was performed using Western blot, immunofluorescence, qRT-PCR, toe thickness measurement, and H&E staining of the plantar skin sections. CAPE administration produced significant reductions in CFA-induced pain and anxiety-like behaviors. Intraperitoneal administration of CAPE significantly suppressed the phosphorylation of PI3K, Akt, and NF-κB in microglia, reduced the expression of M1 microglial marker CD86 and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and increased the expression of M2 marker CD206 and anti-inflammatory cytokines (IL-4, IL-10). Additionally, CAPE reduced paw edema and inflammatory factor levels in toe tissue. In vitro experiments further confirmed that CAPE induced the polarization of microglia from the M1 to M2 phenotype. Our results demonstrate that CAPE facilitates the transition of microglia to the M2 phenotype mediated by the PI3K/Akt/NF-κB pathway, which attenuates peripheral inflammation and subsequently diminishes inflammation-induced hypersensitivity. These results offer novel perspectives on the possible therapeutic applications of CAPE in the management of inflammatory pain.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251410746"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12847659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892715","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":"Intraindividual pain variability in chronic pain: A systematic review.","authors":"Julie Klinke, Valentina Molinari, Karin Jensen","doi":"10.1177/17448069261439609","DOIUrl":"10.1177/17448069261439609","url":null,"abstract":"<p><strong>Objective: </strong>To present the first systematic review on the empirical evidence for variations in intraindividual pain intensity in patients with long-term pain conditions.</p><p><strong>Methods: </strong>The search was conducted on Medline and included prospective longitudinal non-interventional studies done on adult human subjects with chronic pain conditions linked to nociplastic pain mechanisms. Abstract screening and full-text review were performed by two independent reviewers. A third reviewer was consulted in case of disagreement.</p><p><strong>Results: </strong>Of the 1195 results, 13 studies fulfilled the eligibility criteria as determined by abstract screening and full-text review performed by two independent reviewers. Studies included patients with fibromyalgia, low back pain, temporomandibular disorder and, because of the growing evidence for central sensitization, osteoarthritis. Findings showed consistent evidence of intraindividual pain variability in patients with nociplastic pain, regardless of diagnosis. In several studies, it was possible to cluster patients based on degree of pain variability.</p><p><strong>Conclusions: </strong>Our findings provide evidence of intraindividual variability in pain intensity in patients with pain conditions that includes nociplastic pain mechanisms, regardless of precise diagnosis. Preliminary evidence suggests that degree of intraindividual pain variability may be associated with measures of clinical relevance, including mental health, fatigue, physical activity level, and drug and placebo response.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261439609"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639476","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}

{"title":"Lithium prevents the neurotoxic effects of paclitaxel mediated through TRPA1 channels.","authors":"Julio C Sánchez, Aníbal Valencia-Vásquez, Juan C Olaya, Alexander Alemán, Jenifer Guerrero, Martín Torres, Luís F Martínez, Laura V Muñoz","doi":"10.1177/17448069251410396","DOIUrl":"10.1177/17448069251410396","url":null,"abstract":"<p><p>Paclitaxel (PTX) is a drug commonly used in cancer chemotherapy despite its neurotoxicity. TRPA1 channels are essential mediators of sensory transduction and nociception. These cation channels are linked to PTX-induced neurotoxicity, which Li⁺ prevents. This study aimed to examine the effects of Li+ on PTX-induced neurotoxicity and on TRPA1 channels. We utilized the SH-SY5Y cell line to assess cell viability via the MTT assay. Intracellular Ca²⁺ concentration in Fura-2-loaded cells was measured using spectrofluorometry. TRPA1 channel activity was evaluated with whole-cell patch-clamp recordings. The effects of PTX, Li⁺, and TRPA1 agonists and antagonists were tested. Motor function, thermal response, and cognitive performance were assessed in adult Wistar rats with neuropathy induced by PTX. PTX (100 nM) significantly reduced cell viability, and Li⁺ (10 mM) alleviated this effect. AITC (300 µM), a TRPA1-selective agonist, decreased cell viability, with a more pronounced impact when PTX was present. A967079 (10 µM), a selective TRPA1 antagonist, significantly lessened the cytotoxicity caused by PTX. Li⁺ reduced the cytotoxic effects of TRPA1 activation both with and without PTX. PTX increased TRPA1 currents and amplified TRPA1-mediated intracellular Ca²⁺ increase, while Li⁺ neutralized both effects. Additionally, PTX causes sensorimotor and cognitive neuropathy, which was reversed by Li⁺ treatment. These findings suggest that Li⁺ may act as a neuroprotective agent, preventing neuronal damage caused by PTX via TRPA1 channel pathways.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251410396"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724312","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":"Spinal overexpression of CAPN1 in CaMKII neurons mediates paclitaxel-induced neuropathic pain via NCS-1-TRPV4 signaling.","authors":"Ya-Ning Zhang, Shao-Xia Chen, Qiao-Yun Li, Jia-Qi You, Yao-Hui Zhou, Ying Zang","doi":"10.1177/17448069251413873","DOIUrl":"10.1177/17448069251413873","url":null,"abstract":"<p><strong>Background: </strong>Paclitaxel (PTX), a widely administered chemotherapeutic drug, is known to cause neuropathic pain as a severe adverse effect. Elevated calpain expression in tumor tissues not only mediates chemoresistance but may also participate in the paclitaxel-induced neuropathic pain (PINP). There is still controversy over whether Calpain-1 (CAPN1), a subtype of calpain protease, exerts neuroprotective effects or nociceptive effects. The role and underlying mechanism of calpain1 in PINP remain unclear.</p><p><strong>Results: </strong>To clarify the contribution of calpain to CIPN, we examined the protein expressions of CAPN1, CAPN2, Neuronal Calcium Sensor-1(NCS-1), and Transient Receptor Potential Vanilloid 4 (TRPV4) in the DRGs and spinal dorsal horn (SDH) of PTX-treated rats. Results showed no significant changes in CAPN1 and CAPN2 protein levels in the DRGs, but marked upregulation in the SDH, along with heightened calpain activity, as evidenced by the accumulation of spectrin degradation products (a known substrate of calpain). The abnormal enhancement of CAPN1 in PTX-treated rats, contrasting with its reduced expression in most chronic pain models, prompted further investigation into its potential involvement in chronic pain. Immunofluorescence double-staining confirmed that CAPN1 localization was predominantly neuronal. Intraspinal CAPN1 overexpression restricted to CaMKII neurons in the naive rats effectively reproduced paclitaxel-induced neuropathic pain (PINP) with a comparable extent and duration of pain threshold reduction. Western blot analysis revealed that CAPN1 overexpression in spinal CaMKII neurons elevated NCS-1 expression, a calcium-binding protein essential for maintaining calcium homeostasis, which in turn strengthen the expression of CAPN2 as well as the calpain enzymatic activity. These data indicate that CAPN1 does not confer neuroprotective effects in paclitaxel-induced pain models. Rather, its overexpression in spinal CaMKII neurons directly promotes nociceptive signaling, most likely through disruption of plasma membrane calcium dynamics. Collectively, the results identify CAPN1 as a candidate therapeutic target for the clinical treatment and prevention of PINP.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251413873"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12855738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892739","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":"T cells modulate the development and maintenance of painful paclitaxel-induced peripheral neuropathy in RNU rats.","authors":"Ahmed Olalekan Bakare, Gerard Limerick, Vasudha Goel, Ratan K Banik, Lei Zheng, Andrew J Shepherd, Kristine Glunde, Qin Zheng, Eellan Sivanesan","doi":"10.1177/17448069261418431","DOIUrl":"10.1177/17448069261418431","url":null,"abstract":"<p><p>The role of T cells in chemotherapy-induced peripheral neuropathy (CIPN) is complex and shaped by biological and experimental factors, including sex, hormonal status, genetic background, and cancer model. This complexity has contributed to inconsistent findings among studies, limiting therapeutic progress. In this study, we investigate how T cells contribute to painful paclitaxel (PTX)-induced peripheral neuropathy (PIPN). Adult male T cell-competent (RNU^+/-) and T cell-deficient (RNU^-/-) rats were subcutaneously inoculated with tumor cells and subsequently treated with intraperitoneal PTX (8 mg/kg total dose). Reflexive (mechanical, heat, cold) and non-reflexive (burrowing, gait) pain behaviors were assessed from baseline through week 6. Immunohistochemistry (CD68, CX3CR1, CD206) and flow cytometry (CD163, CD86, CD11b/c, CD3, CD161a, CD45RA) were used to assess macrophage and lymphocyte populations. T cell-competent, but not -deficient, rats developed and maintained cold hypersensitivity following PTX. T cells also reduced the onset intensity of PTX-induced mechanical hypersensitivity. In T cell-competent rats, PTX reduced T and B cell counts and increased the CD4+/CD8+ T cell ratio across DRG, sciatic nerve, and spleen. PTX shifted macrophage polarization toward the M1 phenotype and reduced the M2/M1 ratio, independent of T cells. However, M2 macrophages (M2γ and M2a) increased specifically in the sciatic nerves of T cell-deficient rats. Additionally, natural killer (NK) cells decreased in PTX-treated, T cell-deficient rats but remained unchanged in T cell-competent rats. These findings highlight the complex role of T cells in PIPN. In PIPN, T cells play a critical role in driving PTX-induced cold hypersensitivity. A decrease in their number worsens pain intensity, possibly by altering the CD4+/CD8+ T cell balance. In contrast, NK cell reductions in T cell-deficient rats may contribute to hypersensitivity in the absence of T cells.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261418431"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12886724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966517","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":"Consensus co-expression analysis identifies a common set of co-expressed genes associated with diabetic peripheral neuropathy and chemotherapy-induced peripheral neuropathy.","authors":"Kord M Kober, Esther Chavez-Iglesias, Nam Woo Cho, Sue S Yom, Niharika Dixit, Marina Sirota, Alexandre Chan, Adam Olshen","doi":"10.1177/17448069261435315","DOIUrl":"10.1177/17448069261435315","url":null,"abstract":"<p><strong>Background: </strong>Diabetic peripheral neuropathy (DPN) and chemotherapy-induced peripheral neuropathy (CIPN) are major clinical challenges with limited therapeutic options. While these conditions arise from different causes, they may share common molecular mechanisms that could be targeted for intervention.</p><p><strong>Methods: </strong>We performed consensus weighted gene co-expression network analysis (WGCNA) on two publicly available datasets: GSE185011 (DPN vs healthy controls in peripheral blood mononuclear cells) and GSE173610 (paclitaxel-treated vs control iPSC-derived sensory neurons). After filtering all but the most variable genes, consensus analysis was used to identify conserved co-expression modules across both conditions.</p><p><strong>Results: </strong>Consensus analysis identified a 193-gene module (ME3/brown) significantly associated with both DPN (correlation = 0.817, <i>p</i> = 0.0040) and CIPN (correlation = 0.971, <i>p</i> = 0.0060). Functional enrichment analysis of this module revealed pathways related to Glycolysis, FoxO signaling, Apoptosis, and Autophagy.</p><p><strong>Conclusions: </strong>Our analysis reveals a convergent molecular signature underlying both DPN and CIPN, centered on metabolic reprogramming, transcriptional stress, and programmed cell death. These findings provide a systems-level framework for developing therapies targeting shared pathological mechanisms.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261435315"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13039646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444187","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":"Orbital tightening assessment to evaluate pain and physical discomfort in chlorine-exposed rats: A machine learning based measurement approach.","authors":"Saurav Gupta, Wesam Nasser, Gajanan R Jadhav, Amber J Johns, Iram Zafar, Aftab Ahmad, Jianguo Gu, Shama Ahmad","doi":"10.1177/17448069251410828","DOIUrl":"10.1177/17448069251410828","url":null,"abstract":"<p><p>Noxious chemicals like chlorine induce extreme distress, pain, and irritation in exposed individuals, yet methods to evaluate pain-related behavioral responses are absent. It is also unknown whether analgesics would alleviate pain and physical discomfort induced by such noxious chemicals. The grimace scale (GS), which evaluates facial expression features such as orbital tightening (OT), is a valuable indicator of pain and distress in animals. However, conventional GS approaches are labor-intensive, prone to subjectivity, and lack quantitative precision. In this study, we employed machine learning with DeepLabCut to annotate key facial landmarks in video recordings of chlorine-exposed rats. Focusing on the superior and inferior eyelid margins and the medial and lateral canthi, we quantified eyelid distance and palpebral fissure width as measures of OT. Rigorous inclusion and exclusion criteria for annotated images were established to ensure accuracy and reproducibility. The quantitative GS in rats subjected to chlorine exposure was validated. Significant reductions in eyelid distance and palpebral fissure width were observed upon chlorine exposure as compared to unexposed control animals. Administration of the opioid analgesic buprenorphine significantly reduced the OT caused by chlorine. This study establishes a robust, quantitative method for assessing OT in chlorine-exposed rats using DeepLabCut, providing a scalable, objective tool for assessing pain induced by noxious chemicals in preclinical research. This study also suggests that opioids can alleviate pain and physical discomfort induced by inhalation of noxious chemicals, providing a new therapeutic strategy for managing the respiratory hazard of noxious chemicals.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251410828"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12812198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743391","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":"Assessment of pruritogen-induced responses in the glabrous skin of mice.","authors":"Shuang Wu, Haley Steele, Katy Lawson, Ryan Stewart, Liang Han","doi":"10.1177/17448069261420554","DOIUrl":"10.1177/17448069261420554","url":null,"abstract":"<p><p>Chronic itch is a debilitating symptom associated with many dermatological and systemic diseases. Rodent behavioral models that distinguish pain and itch responses remain limited. Our previous studies have examined behavioral responses of mice to chemicals delivered to the plantar glabrous skin and suggested that glabrous skin biting is associated with itch sensation whereas licking represents pain sensation, establishing a new mouse behavioral model to differentiate pain and itch responses in the glabrous skin. To provide further validation of this model, we here investigated behavioral responses following intraplantar injection of multiple pruritogens to examine if they can effectively evoke biting behavior. We show that most of the tested pruritogens induced dose-dependent responses. PAR2 peptide agonist SLIGRL selectively evoked licking, whereas deoxycholic acid (DCA) selectively induced biting. 5-HT triggered licking with a low concentration and both licking and biting with a higher concentration. IL-31, allergen ovalbumin, and mast cell degranulator compound 48/80 evoked both licking and biting. Importantly, morphine abolished capsaicin-induced licking but not biting induced by Bam8-22 or DCA, confirming that glabrous skin biting represents an itch-associated nocifensive behavior. Together, our results establish a robust model to differentiate between pain and itch and provide a platform for investigating mechanisms underlying glabrous skin itch.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261420554"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13009572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041445","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":"Mitochondrial DAMPs produce inflammatory hyperalgesia via stimulator of interferon genes (STING) activation in DRG neurons.","authors":"Hiroaki Amino, Ayaka Higashi, Shunsuke Yamakita, Yasuhiko Horii, Fumimasa Amaya","doi":"10.1177/17448069261435322","DOIUrl":"10.1177/17448069261435322","url":null,"abstract":"<p><p>Damage-associated molecular patterns (DAMPs), including mitochondria-derived molecules, are known to trigger immune responses and produce nociceptor sensitization during tissue inflammation. This animal study investigated whether mitochondrial debris promotes inflammatory hyperalgesia through activation of the stimulator of interferon genes (STING) signaling pathway in dorsal root ganglion (DRG) neurons. The results showed that local administration of mitochondrial debris into the hind paws of rats induced significant mechanical hyperalgesia and increased STING expression in DRG neurons. Pretreatment with H-151, a selective STING inhibitor, attenuated both debris-induced hyperalgesia and neuronal STING upregulation. STING expression in DRG neurons was similarly upregulated in a model of tissue inflammation induced by Complete Freund's Adjuvant (CFA), and administration of H-151 significantly alleviated the inflammatory hyperalgesia and increase in STING expression. These findings suggest that mitochondrial debris released during tissue inflammation activates the STING pathway in primary afferent neurons. Effective suppression of hyperalgesia by pharmacological inhibition of STING in both debris-induced and CFA-induced models in this study highlights the pronociceptive role of STING activation in peripheral sensory neurons. In conclusion, mitochondrial debris-induced STING activation in DRG neurons plays a critical role in the development of inflammatory hyperalgesia, and targeting this pathway might represent a novel therapeutic strategy for inflammatory pain.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261435322"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13039647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444270","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}