Molecular Pain最新文献

{"title":"Mechanical needling and sterile water hydrodissection modulate nociception via extracellular matrix perturbation and ion channels.","authors":"Carl Pc Chen, Areerat Suputtitada","doi":"10.1177/17448069261453185","DOIUrl":"10.1177/17448069261453185","url":null,"abstract":"<p><strong>Background: </strong>Musculoskeletal disorders are increasingly recognized as conditions involving extracellular matrix dysregulation, characterized by fibrosis, calcification, fascial adhesions, and altered nociceptor signaling. These features highlight the role of mechanobiology in pain generation and modulation. Ultrasound-guided hydrodissection has emerged as an intervention capable of perturbing the extracellular microenvironment, with potential downstream effects on nociceptive pathways.</p><p><strong>Methods: </strong>A structured literature search was conducted across PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library (January 2000-March 2026) to identify clinical and mechanistic studies investigating ultrasound-guided hydrodissection, mechanical needling, and sterile water injection. Eligible studies were synthesized qualitatively.</p><p><strong>Results: </strong>Thirty studies were included, encompassing randomized trials, observational studies, and mechanistic investigations across multiple pain conditions. Evidence suggests that mechanical and osmotic perturbation of the extracellular matrix may disrupt fibrotic architecture, facilitate fascial plane separation, and modify the local biochemical microenvironment. Hypotonic sterile water has been associated with activation of mechanosensitive and osmosensitive ion channels, including TRPV1, PIEZO1/2, and ASIC, leading to calcium influx-mediated modulation of neuronal excitability. These processes may contribute to peripheral and central nociceptive modulation through integrated mechanobiological and microvascular mechanisms.</p><p><strong>Conclusions: </strong>Ultrasound-guided mechanical needling with sterile water hydrodissection represents a mechanobiological approach to modulating nociceptive signaling through extracellular matrix perturbation and ion channel activation. This framework provides a translational basis for targeting structural and microenvironmental contributors to pain.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261453185"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13261019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147931538","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":"RIN1 inhibited TRPV1-dependent pain sensitization in a mouse model of bone cancer pain.","authors":"Yue Zhang, Hai-Feng Jiang, Ya-Ni Guo, Shao-Shan Wang, Xiang-Ru Zeng, Kang-Li Wang, Chao-Jun Wei, Xiao-Dong Hu","doi":"10.1177/17448069261456866","DOIUrl":"10.1177/17448069261456866","url":null,"abstract":"<p><p>The Ras and Rab interactor 1 (RIN1) is a multifunctional signaling protein that has been implicated in the regulation of tumor cell migration and proliferation. Here we found that RIN1 was abundant in the dorsal root ganglia (DRG) neurons positive for transient receptor potential vanilloid 1 (TRPV1), a critical mediator of pain sensitization in patients with metastatic bone cancer. Our data showed that RIN1 interacted with TRPV1 and induced the endocytosis of TRPV1 through its guanine nucleotide exchange factor activity toward small GTPase Ras-related protein 5 (Rab5). This process limited the duration and magnitude of TRPV1-dependent acute pain responses in intact male mice. Conditioned knockout of RIN1 in the DRG neurons enhanced TRPV1 activity and led to the reflexive nociceptive sensitization and aversive pain behaviors. In mice with the bone cancer pain, we found a significant reduction of RIN1 protein level in the DRG neurons, which correlated with TRPV1 accumulation on the plasma membrane. Special rescue of RIN1 expression in the DRG neurons repressed the surface TRPV1 distribution and alleviated both the reflexive-defensive and affective-motivational aspects of bone cancer pain. Our data thus revealed an important role of RIN1 in the negative control over TRPV1-dependent pain behaviors.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261456866"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13342426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148016510","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":"Olfactory ensheathing cell transplantation targets macrophage extracellular traps and NKCC1 to alleviate pain after spinal cord injury.","authors":"Honghui Lei, Tao Liu, Fangyong Wang, Yang Yu, Sitong Su","doi":"10.1177/17448069261452906","DOIUrl":"10.1177/17448069261452906","url":null,"abstract":"<p><p>Spinal cord injury (SCI) triggers neuropathic pain through inflammatory secondary injury. Olfactory ensheathing cells (OECs) hold therapeutic promise, but their pain-relieving mechanisms are unclear. This study investigated whether OEC transplantation alleviates pain by modulating macrophage extracellular trap (MET) formation and Na⁺-K⁺-Cl^- cotransporter 1 (NKCC1) expression. Following ethical approval, a rat contusive SCI model was established. OEC-treated rats received a cell transplant post-injury. Motor and sensory functions were assessed over 35 days. Tissue was analyzed for NKCC1, CD68, and the MET marker H3Cit. In vitro, RAW264.7 macrophages were stimulated with TNF-α to induce METs. OEC transplantation significantly improved functional recovery and reduced mechanical/thermal hypersensitivity. Histology showed preserved tissue structure. Critically, OEC treatment suppressed MET formation (reduced H3Cit/CD68) and downregulated NKCC1 in vivo. In vitro, OEC-conditioned medium inhibited TNF‑α‑induced MET formation and NKCC1 expression in macrophages. Thus, OECs alleviate neuropathic pain and promote recovery after SCI by coordinately suppressing macrophage extracellular traps and regulating NKCC1 expression, revealing a novel immunomodulatory‑ion transport axis for pain intervention.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261452906"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13260965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147868986","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":"Dezocine alleviates cancer-induced bone pain and suppresses intraosseous tumor growth in renal cell carcinoma via the NAMPT/NAD+ axis.","authors":"Lijun Huang, Cixian Hu, Ya Shao, Liming Zhao","doi":"10.1177/17448069261460286","DOIUrl":"10.1177/17448069261460286","url":null,"abstract":"<p><p>Bone metastasis-associated pain is a major cause of morbidity in advanced renal cell carcinoma (RCC), and effective therapies that concurrently mitigate pain and intraosseous tumor burden remain limited. Here, we evaluated dezocine as a potential dual-action agent and explored the involvement of the NAMPT/NAD⁺ axis. In 786-O cells, dezocine dose-dependently suppressed proliferation (IC₅₀ = 73.6 μM), clonogenicity and increased apoptosis, accompanied by reduced NAMPT expression and a decreased NAD⁺/NADH ratio. Pharmacological rescue with the NAMPT activator SBI-797812 partially reversed these effects. In vivo, using an intra-tibial RCC cell inoculation model that recapitulates osteolysis and cancer-induced bone pain (CIBP), dezocine alleviated mechanical allodynia and thermal hyperalgesia, and reduced osteolytic bone destruction and intraosseous tumor progression; co-administration of SBI-797812 partially attenuated these effects (<i>n</i> = 6). Tumor tissues from dezocine-treated mice showed decreased Ki67 and NAMPT, increased cleaved caspase-3, and enhanced AMPK phosphorylation, consistent with metabolic stress-associated apoptosis. Collectively, these findings suggest that dezocine may provide dual analgesic and antitumor benefits in intraosseous RCC lesions, at least in part by suppressing the NAMPT/NAD⁺ axis, supporting further translational evaluation for bone metastasis-associated pain management.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261460286"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13269969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148163811","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":"Stimulation of spinal afferents from skin activates parabrachial neurons that respond to taste.","authors":"Jinrong Li, Christian H Lemon","doi":"10.1177/17448069261460644","DOIUrl":"10.1177/17448069261460644","url":null,"abstract":"<p><p>The parabrachial (PB) nucleus participates in neural coding for diverse sensory modalities, including nociception and taste. Recent neurophysiological studies identified a subpopulation of PB neurons that responds to both gustatory and oral nociceptive (trigeminal) stimuli. These taste-integrative neurons populate PB subnuclei that receive somatosensory input from bodily skin supplied by spinal afferents. Yet whether spinal sensory input can excite these cells was unexplored. Here, we applied electrophysiological and optogenetic techniques in anesthetized TRPV1; Ai32 mice, which support transdermal photoexcitation of cutaneous TRPV1-lineage thermo-nociceptive fibers, to study if spinal sensory stimulation could engage taste-active PB cells. Action potentials were monitored in isolated PB neurons during oral application of diverse taste and chemesthetic stimuli, oral thermal stimulation using temperature-controlled water, and pinch of the hindpaw and tail. In some cases, photostimulation was applied to pinch-sensitive receptive fields to optogenetically excite bodily TRPV1-lineage fibers. Analysis of 94 PB neurons identified 35 cells (37.2%) that responded to more than one stimulus modality, including 10 taste-excited neurons that also fired impulses to noxious oral chemesthetic (trigeminal) stimuli, oral thermal input, and hindpaw/tail pinch. Such neurons could also respond to photoexcitation of TRPV1-lineage afferents innervating body extremities and frequently displayed bitter-oriented (aversive) taste response profiles. These data suggest that spinal afferent input, including pain-related neural messages from skin, converges onto taste-active PB neurons. These neurons would be misclassified as unimodal \"taste\" cells under traditional methods but display multisensory response repertoires that agree with involvement of PB circuits in sensory-affective processing.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261460644"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13305291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148176005","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":"Mast cell-5-HT-HTR2A axis involvement in chronic itch induced by SADBE.","authors":"Limin Fan, Xiuyu Nong, Manting Ni, Xi Chen, Liping Zeng, Huifang Chen, Jian Wang, Xuan Ouyang, Ailin Tao, Xueting Liu","doi":"10.1177/17448069251410452","DOIUrl":"10.1177/17448069251410452","url":null,"abstract":"<p><p>Although 5-hydroxytryptamine (5-HT) contributes to pruritus associated with allergic contact dermatitis (ACD), the role of 5-HT derived from mast cells (MC) in chronic pruritus induced by squaric acid dibutyl ester (SADBE), and the expression and distribution of 5-HT2A receptor (HTR2A) in sensory neurons remain unclear. In this study, a SADBE-induced ACD mouse model was established to evaluate pruritus behavior, MC activation, and 5-HTproduction. The mechanism was verified through pharmacological intervention (MC stabilizer cromolyn, HTR2A antagonist Ketanserin) and FcεRIα-KO mice. It was found that SADBE triggered time-dependent MC recruitment (peaking at Day 14-21) and Mc-derived 5-HT release, which were associated with persistent pruritus. The intervention of MC stabilizer cromolyn and FcεRIα-KO mice confirmed MC/IgE-dependent 5-HT release, and inhibiting MC degranulation could reduce pruritus. Single-cell RNA sequencing and RNAscope in situ hybridization techniques revealed that HTR2A was mainly expressed in the NF3/PEP2/NP3 subsets of DRG neurons. The co-expression level of HTR2A and Nppb was relatively high, partially overlapping with TRPV1/TRPA1. HTR2A antagonists can relieve SADBE-induced pruritus. In conclusion, we have determined that the MC-5-HT-HTR2A axis is involved in chronic pruritus in SADBE-induced ACD, and targeting this axis provides a very promising therapeutic strategy.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251410452"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12833167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724327","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":"Biphasic synaptic plasticity of the medial thalamic-cingulate pathway contributes to pain hypersensitivity in vivo.","authors":"Shen Lin, Shun Hao, Yi Wu, Weiqi Liu, Jihua Wang, Le Li, Wanfen Liu, Min Zhuo, Wucheng Tao","doi":"10.1177/17448069261466896","DOIUrl":"10.1177/17448069261466896","url":null,"abstract":"<p><p>Central synaptic plasticity is a key mechanism for long-term memory and chronic pain. The anterior cingulate cortex (ACC), a critical cortex area for pain perception, receives sensory inputs from the thalamus. Although many studies have demonstrated that synaptic transmission in the ACC is potentiated in different chronic pain models, there are few studies investigating synaptic changes of the thalamus-ACC pathway in vivo. Here we selectively stimulated the thalamus-ACC pathway by using optogenetic approach in adult mice both in vitro and in vivo. Theta burst stimulation (TBS) induced robust and long-lasting long-term potentiation (LTP) in the medial thalamus-ACC pathway in the ACC of adult mice in vitro. The potentiation lasted for at least 2 to 3 hrs after the induction, and some of silent responses were recruited. In freely moving adult mice, the same stimulation of the medial thalamus-ACC pathway induced rapid and long-lasting potentiation of synaptic responses in the ACC of adult mice in vivo. This potentiation lasted for days and weeks, at least six weeks after the induction in vivo. In parallel, behavioral sensory responses to noxious mechanical and thermal stimuli were sensitized in the same animals while anxiety-like behaviors were not significantly affected. Furthermore, low-frequency stimulation induced long-term depression (LTD) in the ACC, and reversed mechanical and thermal sensitization in animals with LTP. Our results provide strong evidence that biphasic synaptic plasticity (LTP and LTD) of the thalamus-ACC pathway contributes to behavioral sensitization after peripheral injury, and understanding the mechanisms for such LTP may help future treatment of chronic pain in patients and pets.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261466896"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13447995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148448091","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":"Static and dynamic perspective on brain activity and functional connectivity alternations in the comorbidity of chronic pain and depression: An fMRI study in rats.","authors":"Jie Deng, Hai-Ting Fan, Yu-Ting Zhao, Yu-Juan Duan, Cui-Cui Liu, Di-Han Lu, Xiang-Zhong Zhang, Wen-Jun Xin, Xia Feng, Ting Xu","doi":"10.1177/17448069261443836","DOIUrl":"10.1177/17448069261443836","url":null,"abstract":"<p><strong>Background: </strong>Clinically, chronic pain and depression often coexist in multiple diseases and reciprocally reinforce each other, which greatly escalates the difficulty of treatment. The alteration in neural networks underlying the chronic pain/depression comorbidity remains unclear.</p><p><strong>Methods: </strong>Spared nerve injury (SNI) was performed to establish a rat model of comorbidity of chronic pain and depression. Multimodal fMRI was utilized to acquire neuroimaging data of the rat brain, with BOLD and DTI data used to analyze adaptive changes in brain regions and networks associated with comorbidity.</p><p><strong>Results: </strong>By integrating static and dynamic ALFF analyses with DTI parameters, six key brain regions (OFR_L, CA1_L, CA3_L, PL_L, Stri_L, and Stri_R) were identified. These regions showed significant associations with both pain-related and depressive-like behaviors and formed a comorbidity-related network centered on the prefrontal cortex, hippocampus, striatum, and primary sensory cortex. Further analyses indicated that the relationship between fMRI features and depressive-like behavior was largely mediated by pain-related processes.</p><p><strong>Conclusions: </strong>This study reveals network-level neural alterations underlying chronic pain-depression comorbidity and supports a pain-mediated pathway linking brain activity to affective disturbances. These findings provide new insights into the neural mechanisms of this comorbidity and highlight the importance of integrated pain-depression interactions.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261443836"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633869","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":"Whole-blood miRNA candidate prioritization for longitudinal pain change suggests synaptic and neuronal organization pathway involvement in early rheumatoid arthritis.","authors":"Heejeong Shin, Jaeuk Kim, Seung-Nam Kim","doi":"10.1177/17448069261487017","DOIUrl":"10.1177/17448069261487017","url":null,"abstract":"<p><p>Pain is a major clinical outcome in chronic inflammatory disease, yet molecular correlates of within-person pain change remain unclear and must be distinguished from inflammatory change. We used longitudinal whole-blood multi-omics data from the RA-MAP/TACERA early rheumatoid arthritis cohort to prioritize microRNA (miRNA) candidates whose 6-month changes co-varied with change in visual analogue scale pain (ΔVAS). Among 151 participants and 1,881 miRNA features, we applied a stability-oriented delta-omics workflow combining subsampling elastic-net selection frequency, bootstrap directional filtering, and post-selection rank-residual partial correlation adjusted for ΔCRP and ΔESR. This identified 29 directionally stable miRNA candidates; after ΔCRP/ΔESR adjustment, 16 retained sign-consistent support at post-selection BH-FDR < 0.05 within these 29 candidates. Matched miRNA-mRNA delta analysis found no individual miRNA-mRNA pair surviving pair-level BH-FDR correction. At the primary nominal pair-selection threshold of p < 0.05, 123 inverse pairs involving 117 target genes yielded exploratory Gene Ontology Biological Process enrichment involving synaptic and neuronal organization; however, no GO term remained BH-significant when the pair-selection threshold was tightened to p < 0.01. The exploratory plasma chronic neck pain comparison yielded 22 of 39 sign-consistent assay matches (56.4%; exact 95% CI, 39.6%-72.2%), which was not statistically distinguishable from the 50% chance expectation, and no match survived BH-FDR correction. These findings outline a stability-oriented, inflammation-adjusted approach for prioritizing blood miRNA candidates linked to pain change. The 16-miRNA subset should be interpreted as a hypothesis-generating candidate pool rather than a validated biomarker panel and provides a focused basis for future longitudinal validation and functional studies.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"22 ","pages":"17448069261487017"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891774","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":"Zerumbone alleviates TRESK- and TRPV1-mediated ion currents and reduces excitability of human iPSC-derived nociceptor-like neurons.","authors":"Naomi Hoerdler, Angelique Grell, Saheli Chatterjee, Erhard Wischmeyer, Beatrice A Nossek, Oliver Dräger","doi":"10.1177/17448069261492873","DOIUrl":"https://doi.org/10.1177/17448069261492873","url":null,"abstract":"<p><p>Secondary plant metabolites are widely used in traditional and naturopathic medicine to treat pain, infection, and inflammation. The sesquiterpenoid zerumbone, derived from the edible ginger <i>Zingiber zerumbet</i>, has been shown to exert analgesic, antioxidant, antitumoral, and antimicrobial effects in preclinical models, acting through multiple receptor systems including cannabinoid (CB) receptors, peroxisome proliferator-activated receptors, N-methyl-D-aspartate (NMDA) receptors, and the serotonergic system. Zerumbone also modulates inflammatory and nitric oxide-cGMP-K⁺ATP signaling pathways implicated in antiallodynic responses, yet its direct impact on nociceptor-associated ion channels like the Transient receptor potential vanilloid 1 (TRPV1) and the Twik-related spinal cord potassium channel (TRESK) in human cellular systems remains poorly characterized. In the present study, the antinociceptive properties of zerumbone were investigated in human HEK293-based and induced pluripotent stem cell (iPSC)-derived nociceptor models. Here, the zerumbone treatment reduced cell viability and proliferation in a concentration-dependent manner without altering TRPV1 or TRESK protein expression. Whole-cell patch-clamp recordings revealed that zerumbone reversibly inhibited TRESK-mediated outward potassium currents upon direct application, whereas bath-applied zerumbone increased outward currents, suggesting context-dependent modulation. In TRPV1-expressing HEK293 cells, SH-SY5Y neuroblastoma cells, and human iPSC-derived nociceptors, zerumbone reduced TRPV1-mediated ion currents and capsaicin-evoked calcium signals, indicating a direct or competitive inhibitory effect on TRPV1 activity. In iPSC-derived nociceptors, zerumbone decreased action potential firing at moderate depolarizing currents, shifted the resting membrane potential, and increased rheobase, consistent with reduced nociceptor excitability, while no significant changes in TRESK-mediated currents were detected. These data suggest that zerumbone attenuates human iPSC-derived nociceptor-like neuron excitability largely via TRPV1 inhibition, with a more complex, concentration- and application-method-dependent modulation of TRESK. The findings provide a mechanistic basis for the antiallodynic effects of zerumbone observed in rodent models and highlight the need for further studies in human-derived systems to clarify the precise channel-level interactions and their relevance to inflammatory and neuropathic pain.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"22 ","pages":"17448069261492873"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137563","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}