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":"Metformin exhibits analgesic activity in neuronal cell models and CFA-induced inflammatory pain in mice.","authors":"Thi-Chau-Loan Phan, Jui-Ting Chang, Chih-Hsiang Ma, Yao-Jen Liang","doi":"10.1177/17448069261452893","DOIUrl":"10.1177/17448069261452893","url":null,"abstract":"<p><p>Inflammatory pain is mediated by complex interactions between immune signaling and sensory neurons, with prostaglandin E2-dependent pathways playing a central role in nociceptive sensitization. Metformin, a first-line antidiabetic drug, has emerged as a potential non-opioid analgesic due to its pleiotropic anti-inflammatory and neuroprotective properties. In this study, we investigated the analgesic effects of metformin using both an in vitro neuronal sensitization model and an in vivo model of inflammatory pain. In SH-SY5Y neuronal cells, PGE2 exposure significantly reduced Na⁺/K⁺-ATPase activity and increased intracellular cAMP levels. Post-treatment with metformin restored Na⁺/K⁺-ATPase activity and suppressed cAMP elevation in a concentration-dependent manner. In vivo, metformin produced dose-dependent analgesia in mice with complete Freund's adjuvant-induced inflammatory pain, with 0.1 g/kg/day significantly increasing hind paw withdrawal thresholds. Molecular analyses revealed significant downregulation of pain-associated proteins TRPV1 and NaV1.7 in metformin-treated groups, supported by both Western blot and immunohistochemical findings. Histological examination further demonstrated reduced inflammatory cell infiltration and improved tissue recovery. Collectively, these findings indicate that metformin alleviates inflammatory pain by modulating neuronal excitability and inflammatory signaling pathways, highlighting its potential as a non-opioid therapeutic candidate for inflammatory pain management.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261452893"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13305277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147942181","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":"Combination of GABA-derived short peptides and pregabalin in neuropathic pain: In vivo and in silico evaluation.","authors":"Naira H Adamyan, Arusyak G Zhamharyan, Hakob V Topchyan, Tigran K Davtyan, Varduhi H Poghosyan, Knarik M Shamilyan, Sona H Grigoryan, Anush G Tananyan, Maria K Verdyan, Alisa A Chitchiyan, Marine G Balasanyan","doi":"10.1177/17448069261456865","DOIUrl":"10.1177/17448069261456865","url":null,"abstract":"<p><p>Neuropathic pain is a significant clinical issue due to the limited efficacy and adverse effects of existing therapies. This study evaluated the antinociceptive effects of the GABA-derived short peptides pyroglutamylGABA, pyroglutamylGABA ethyl ester, and pyroglutamyl diGABA in combination with pregabalin in a rat model of neuropathic pain induced by chronic constriction injury. Pain-related behavior was assessed using the hot plate test by recording changes in the latency and frequency of licking, jumping, and locomotor activity. Co-administration of peptide-pregabalin combinations modulated nociceptive responses compared with control animals in a time- and compound-dependent manner. The combination of pyroglutamylGABA with pregabalin was associated with increased licking latency and reduced licking frequency, particularly at early time points after injury. The pyroglutamylGABA ethyl ester-pregabalin combination produced the most pronounced effects on jumping-related parameters. A delay in movements was recorded when a combination of pyroglutamyl diGABA and pregabalin was used, whereas all combinations demonstrated increased locomotor activity, suggesting that the antinociceptive effects were not accompanied by the motor suppression typically associated with pregabalin treatment. To explore the potential mechanisms, molecular docking studies were performed targeting key GABAergic system components, including the GAT1 transporter, GABA-AT enzyme, and GABA-B receptors. The investigated peptides demonstrated favorable binding affinities across these targets, suggesting that potential interactions with multiple targets are involved in GABAergic neurotransmission. These findings indicate that the combinations of GABA-derived peptides with pregabalin could be an effective approach in neuropathic pain management. However, further investigation is required to validate these effects and clarify the underlying mechanisms.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261456865"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13269974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148016568","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":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13153499/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Average pain over time, but not current pain, is associated with salivary secretory immunoglobulin a in chronic back pain: A cross-sectional study.","authors":"Adi Shani, Michal Granot, Eilam Palzur, Mariana Agostinho, Roi Treister, Nimrod Rahamimov","doi":"10.1177/17448069261483479","DOIUrl":"10.1177/17448069261483479","url":null,"abstract":"<p><p>Chronic pain is accompanied by widespread physiological dysregulation, yet the mucosal immune system has received little attention. Salivary secretory-immunoglobulin-A (S-IgA) is a non-invasive biomarker of mucosal immunity modulated by sustained stress and autonomic activity. This cross-sectional secondary analysis examined whether pain intensity in chronic back pain is associated with salivary S-IgA in 57 adults enrolled in a parent interventional study (NCT05994118). Pain was assessed on a computerized visual analogue scale (CoVAS, 0-100) at the laboratory visit (current pain and 24-hour average) and via a twice-daily electronic CoVAS diary (1-week, 2-week, and 14-day averages). Two saliva samples collected ∼90 minutes apart were assayed by ELISA, and baseline heart rate variability (HRV) was recorded. Spearman correlations were computed with and without partial adjustment for age, sex, and BMI; Benjamini-Hochberg correction was applied to the ten primary pain × S-IgA tests. Average 24-hour pain was negatively correlated with both S-IgA samples (ρ ≈ -.45 for both, p < .001); the 1-week (ρ ≈ -.34 to -.35, p ≤ .009) and 14-day averages (ρ ≈ -.38 for both, p = .004) showed similar associations. All average-pain associations survived FDR correction and partial adjustment. Current pain was not significantly associated with S-IgA. Baseline high-frequency HRV power was positively associated with S-IgA₁ (ρ = .29, p = .033) but not S-IgA₂. Sustained pain experience, rather than current pain, appears to track salivary mucosal immune function in chronic back pain. However, these hypothesis-generating findings may reflect unmeasured stress- or mood-related confounding, not a pain-specific effect.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"22 ","pages":"17448069261483479"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808829","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":"Pharmacological inhibition of MKP-1 exacerbates central post-stroke pain and neuroinflammation in mice.","authors":"Yong Fei, Xi Meng, Mengjiao Chen, Hanrui Fan, Ping Xu, Mingqing Yu, Haonan Zhang, Yinan Zhang, Fan Bu, Longsheng Xu, Xiang-Yao Li","doi":"10.1177/17448069261484390","DOIUrl":"10.1177/17448069261484390","url":null,"abstract":"<p><p>Central post-stroke pain (CPSP) remains difficult to treat due to limited understanding of its underlying mechanisms. Emerging evidence implicates microglia-driven neuroinflammation in CPSP development. Mitogen-activated protein kinase phosphatase-1 (MKP-1) negatively regulates MAPK signaling and modulates inflammation in neurological disorders, yet its role in CPSP is unclear. Using a mouse model of thalamic hemorrhage, we examined MKP-1 expression and function in CPSP. Behavioral testing assessed pain hypersensitivity and affective disturbances. Immunofluorescence and western blot evaluated MKP-1 expression, microglial activation, and inflammatory signaling in the thalamus. Pharmacological MKP-1 inhibition was employed to assess functional contributions. Thalamic hemorrhage induced persistent mechanical hypersensitivity and anxiety-like behaviors, accompanied by pronounced microglial activation in the peri-lesional thalamus. MKP-1 expression increased significantly after stroke and localized primarily to microglia. MKP-1 inhibition exacerbated pain behaviors and enhanced microglial activation, with corresponding increases in pro-inflammatory mediators and p38 MAPK phosphorylation. These findings suggest that MKP-1 may function as an endogenous negative regulator of microglia-mediated neuroinflammation following thalamic hemorrhage. Pharmacological modulation of MKP-1 signaling warrants further investigation as a potential approach for CPSP.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"22 ","pages":"17448069261484390"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13519224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148830830","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":3.8,"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":"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}