Neurobiology of Pain最新文献_第2页

Neuronal physiology of amygdala neurons in the context of injury and pain 损伤和疼痛背景下杏仁核神经元的神经生理学

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 DOI: 10.1016/j.ynpai.2025.100190

Blesson K Paul, Maria Isabel Nunez-Ordaz, Joseph R. Samuel, Benedict J. Kolber

The amygdala integrates polymodal information including nociceptive stimuli. It is implicated as a key node in regulating both sensory-discriminative and emotional-affective aspects of pain and central sensitization. While central sensitization mechanisms in persistent pain are not completely understood, studying the neuronal properties exhibited by the amygdala neurons within their functional context, in this case, nociception, is important. Such studies can shed light on the behavior-modulating potential of the amygdala. In the last twenty years, multiple laboratories have begun the process of dissecting the cell-type specific activity involved in amygdala function. This review surveys these electrophysiological properties of neurons from different amygdala nuclei, cell types and circuitry studied so far, in the context of nociception and injury. A population-level accounting of these cell types provides greater insight into identifying specific targets to develop interventions for pain-mediated affective conditions.

杏仁核整合包括伤害性刺激在内的多模态信息。它被认为是调节疼痛和中枢敏化的感觉-辨别和情绪-情感方面的关键节点。虽然持续疼痛的中枢致敏机制尚不完全清楚，但研究杏仁核神经元在其功能背景下所表现出的神经元特性，在这种情况下，伤害感觉是很重要的。这样的研究可以阐明杏仁核的行为调节潜能。在过去的二十年中，多个实验室已经开始解剖杏仁核功能中涉及的细胞类型特异性活动的过程。本文综述了迄今为止研究的不同杏仁核神经元的电生理特性、细胞类型和电路，在伤害和损伤的背景下。这些细胞类型的人口水平核算提供了更大的洞察力，以确定特定的目标，以开发干预疼痛介导的情感条件。

引用次数: 0

Individual differences in cognitive performance under pain linked to region-specific alpha power modulations 疼痛下认知表现的个体差异与特定区域的能量调节有关

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 DOI: 10.1016/j.ynpai.2025.100196

Francesca Storey , Mariya Prokhorenko , Michael L. Keaser , Patrick Skippen , Andrew J. Furman , David A. Seminowicz , Ali Mazaheri

Chronic pain is associated with reduced cognitive function, potentially due to a diversion of cognitive resources to processing pain. However, reduced cognitive function during pain is not always consistently evidenced, perhaps due to individual differences in the attentional cost of pain processing. In the current electroencephalography investigation, we therefore examined differences in the top-down modulation of oscillatory activity in a cognitive task, between participants who performed better, and worse, during experimentally induced neuropathic-like pain. We employed a cross-modal attention task in which visual cues indicated whether participants needed to judge the visual orientation or discriminate the auditory pitch of an upcoming target. The visual and auditory targets were presented either simultaneously or individually, enabling us to assess the “cost” of having a distractor present in each modality. Participants engaged in the task under two conditions: prolonged pain via the capsaicin-heat pain model, and pain-free. Participants less “costed” by visual distraction during pain demonstrated a greater increase in alpha power (8–12 Hz) over frontal/central electrodes during pain. This may reflect inhibition of regions related to the processing of painful stimuli (somatosensory cortex), which could increase availability of resources to meet task-demands – a possible task-favouring pattern. In conclusion, our results support the notion that better cognitive function during pain is associated with a behavioral strategy.

慢性疼痛与认知功能下降有关，可能是由于认知资源转移到处理疼痛。然而，疼痛时认知功能的降低并不总是得到一致的证明，这可能是由于疼痛处理的注意成本的个体差异。因此，在当前的脑电图调查中，我们研究了在实验诱导的神经性疼痛中，表现较好和较差的参与者在认知任务中振荡活动自上而下调节的差异。我们采用了一个跨模态注意任务，在这个任务中，视觉线索指示参与者是否需要判断即将到来的目标的视觉方向或辨别听觉音调。视觉和听觉目标同时或单独呈现，使我们能够评估在每种模式中都有一个分心物的“成本”。参与者在两种情况下参与任务：通过辣椒素热疼痛模型延长疼痛和无痛。在疼痛期间，较少“花费”视觉分心的参与者表现出比额叶/中央电极更大的α功率（8-12赫兹）增加。这可能反映了与处理痛苦刺激相关的区域（体感皮层）受到抑制，这可能会增加资源的可用性，以满足任务需求——一种可能的任务偏好模式。总之，我们的研究结果支持这样的观点，即疼痛时更好的认知功能与行为策略有关。

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引用次数: 0

Neutrophil dynamics in surgical wounds – A novel role of interleukin-7 外科伤口中性粒细胞动力学-白细胞介素-7的新作用

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 DOI: 10.1016/j.ynpai.2025.100199

Annika Biesold , Philipp Burkard , Ankita Rawat , Laura Cyran , Patrick Meybohm , Heike Rittner , Michael Briese , Nana-Maria Wagner

Postoperative pain and consequently chronic postsurgical pain remain a significant burden among patients. While neutrophilic granulocytes (neutrophils) are known to play a critical role in wound healing, their precise contribution to pain modulation is not fully understood. The neurotrophin nerve growth factor (NGF), released by fibroblasts and immune cells following injury, is an early mediator of pain development. A companion paper demonstrated that NGF administration to axons of cultured sensory neurons in microfluidic chambers induces upregulation of Il7, encoding interleukin-7 (IL-7). However, its role in neutrophil dynamics within surgical wounds remains broadly unclear. In a murine model of laparotomy, we observed that IL-7 was expressed at wound sites and co-localized with sensory nerve endings and infiltrating neutrophils within 24 h post-surgery. Laparotomy triggered neutrophil mobilization from the bone marrow, leading to an influx of both mature and immature neutrophils into the circulation. Flow cytometric analysis further revealed IL-7 receptor (IL-7R) surface expression on neutrophils, with IL-7 stimulation also enhancing the expression of activation and maturation markers on neutrophils in vitro. These findings suggest that NGF-induced IL-7 release from peripheral nerve terminals represents a novel neuroinflammatory mechanism modulating neutrophil dynamics in the surgical wound, potentially impairing wound healing and exacerbating pain. Therefore, targeting IL-7 signalling in peripheral nerves may offer a promising strategy for improving postoperative pain management.

术后疼痛和慢性术后疼痛仍然是患者的重大负担。虽然中性粒细胞（中性粒细胞）已知在伤口愈合中起关键作用，但它们对疼痛调节的确切贡献尚未完全了解。神经营养因子神经生长因子（NGF）由成纤维细胞和免疫细胞在损伤后释放，是疼痛发展的早期中介。另一篇论文表明，在微流控室中，神经生长因子给予培养的感觉神经元轴突可诱导编码白介素-7 （IL-7）的IL-7上调。然而，它在外科伤口中性粒细胞动力学中的作用仍不清楚。在小鼠剖腹手术模型中，我们观察到IL-7在术后24小时内在伤口部位表达，并与感觉神经末梢和浸润中性粒细胞共定位。剖腹手术触发骨髓中性粒细胞动员，导致成熟和未成熟的中性粒细胞涌入循环。流式细胞分析进一步揭示了IL-7受体（IL-7R）表面在中性粒细胞上的表达，IL-7刺激也增强了体外中性粒细胞活化和成熟标志物的表达。这些发现表明，神经生长因子诱导的周围神经末梢IL-7释放代表了一种新的神经炎症机制，可以调节手术伤口中的中性粒细胞动力学，可能损害伤口愈合并加剧疼痛。因此，靶向周围神经中的IL-7信号可能为改善术后疼痛管理提供了一种有希望的策略。

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引用次数: 0

Editorial commitment to trust and integrity in science: Implications for pain and anesthesiology research 对科学信任和诚信的编辑承诺：对疼痛和麻醉学研究的影响

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 DOI: 10.1016/j.ynpai.2025.100187

Tonya M. Palermo PhD, Didier Bouhassira MD, PhD, Karen D. Davis PhD, FCAHS, FRSC, Hugh C. Hemmings Jr MD, PhD, FRCA, Robert W. Hurley MD, PhD, Joel Katz PhD, Jaideep J. Pandit FRCA, DPhil, DM, MBA, Theodore J. Price PhD, Michael E. Schatman PhD, Stephan K.W. Schwarz MD, PhD, FESAIC, Dennis C. Turk PhD, Marc Van de Velde MD, PhD, EDRA, FESAIC, Matthew D. Wiles MRCP, FCRA, FFICM, Tony L. Yaksh PhD, David Yarnitsky MD

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Unveiling the peripheral nerve hallmarks of chemotherapy-induced neuropathy: insights from paclitaxel treatment in a murine model 揭示化疗引起的神经病变的周围神经特征：来自紫杉醇治疗小鼠模型的见解

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 DOI: 10.1016/j.ynpai.2025.100200

Maria Maiarù , Andrea Petrini , Federica De Angelis , Francesca Nazio , Sara Marinelli

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and debilitating side effect of anticancer drugs like paclitaxel, significantly reducing the quality of life for cancer patients. Paclitaxel-induced peripheral neuropathy (PIPN) is primarily characterized by sensory disturbances such as mechanical allodynia and thermal hyperalgesia. Despite its prevalence, the mechanisms driving PIPN are not fully understood, and current treatment options remain limited. This study explores the impact of varying doses of paclitaxel on neuropathic pain, nerve structural changes, and metabolic alterations in a mouse model. Behavioural assessments demonstrated that paclitaxel induced dose-dependent mechanical allodynia and thermal hyperalgesia, with prolonged symptoms at higher doses. Furthermore, sciatic nerve dysfunction was observed, while metabolic tests revealed significant disruptions in glucose and triglyceride levels, suggesting a link between metabolic imbalances and neuropathy. Histological and molecular analyses identified increased TRPV1 and CGRP expression in skin nerve fibers, accompanied by Schwann cell dysfunction, characterized by myelin disorganization, decreased levels of myelin proteins (P0, MBP), and elevated LC3 levels, pointing to autophagy involvement. Moreover, infiltration of macrophages and mast cells into sciatic nerves indicated an innate immune response. These results emphasize the complex nature of PIPN, which involves sensory nerve sensitization, Schwann cell damage, and metabolic dysregulation. Elucidating these pathways could inform the development of more effective therapies aimed at preventing or alleviating the impact of CIPN.

化疗诱导的周围神经病变（CIPN）是紫杉醇等抗癌药物常见的衰弱性副作用，显著降低癌症患者的生活质量。紫杉醇诱导的周围神经病变（PIPN）主要以感觉障碍为特征，如机械性异常性痛和热痛觉过敏。尽管PIPN很普遍，但其发病机制尚不完全清楚，目前的治疗方案仍然有限。本研究在小鼠模型中探讨了不同剂量紫杉醇对神经性疼痛、神经结构改变和代谢改变的影响。行为评估表明，紫杉醇诱导剂量依赖性机械异常性痛和热痛觉过敏，高剂量时症状延长。此外，观察到坐骨神经功能障碍，而代谢测试显示葡萄糖和甘油三酯水平明显中断，表明代谢失衡与神经病变之间存在联系。组织学和分子分析发现，皮肤神经纤维中TRPV1和CGRP表达增加，伴有雪旺细胞功能障碍，其特征是髓磷脂紊乱，髓磷脂蛋白（P0， MBP）水平降低，LC3水平升高，表明自噬参与。此外，巨噬细胞和肥大细胞浸润坐骨神经表明先天免疫反应。这些结果强调了PIPN的复杂性，包括感觉神经敏化、雪旺细胞损伤和代谢失调。阐明这些途径可以为开发更有效的治疗方法提供信息，旨在预防或减轻CIPN的影响。

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引用次数: 0

Left nucleus accumbens volume is associated with poor sleep in hip osteoarthritis 左伏隔核体积与髋关节骨关节炎患者睡眠质量差有关

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 DOI: 10.1016/j.ynpai.2025.100203

Natalia Egorova-Brumley , Luiza Bonfim Pacheco , Gabby Knox , Leila Nategh , Fiona Dobson , Michelle Hall

Objective

Reduction in the volume of the nucleus accumbens (NAc) has emerged as a promising signature of chronic pain transition, including in osteoarthritis (OA). Yet, less is known about the factors that could influence these changes in the mesolimbic system. Given that poor sleep is common in OA, and recent studies of sleep disturbance on pain perception in animals and healthy populations have specifically implicated the NAc, we hypothesised that the left NAc volume in hip OA would be associated with sleep quality and quantity. Furthermore, we explored how sex interacts with this relationship.

Methods

Cross-sectional study in participants with hip OA (n = 34; aged 60+/-12 years, 67 % females) who reported moderate pain were recruited.

Results

A one-sample t-test showed that the left NAc volumes were significantly lower than normative values (t = -2.7368, df = 33, p-value = 0.009). In a model (F(4, 29) = 6.642, p < 0.001, R2 = 0.4781) including the total intracranial volume (TIV), sex and age, the left NAc volume was significantly predicted by sleep quality (t = -3.416, p = 0.002) assessed with Pittsburgh Sleep Quality Index (PSQI). Sleep efficiency (t = 2.362, p = 0.025) but not hours spent in bed (p > 0.05) was also a significant predictor. With models exploring sleep*sex interactions, only sleep efficiency demonstrated an interaction, suggesting that the left NAc volume is lower in females with worse sleep efficiency (t = -2.086, p = 0.046, albeit not significant when corrected for multiple comparisons, pFDR = 0.138.)

Conclusions

Our results suggest that the reduction of the NAc volumes as a candidate biomarker of pain might be influenced by sleep. This exploratory finding in a chronic hip OA population is consistent with the results previously only reported in animal and experimental pain/sleep studies in healthy participants.

Significance

The left NAc as a candidate biomarker of chronic pain is sensitive to the effects of sleep quality, especially in females with OA.

伏隔核（NAc）体积的减少已成为慢性疼痛过渡的一个有希望的标志，包括骨关节炎（OA）。然而，人们对影响中边缘系统这些变化的因素知之甚少。鉴于睡眠质量差在OA患者中很常见，并且最近在动物和健康人群中关于睡眠障碍对疼痛感知的研究特别涉及了NAc，我们假设髋OA患者左侧NAc体积与睡眠质量和睡眠量有关。此外，我们还探讨了性如何与这种关系相互作用。方法对报告中度疼痛的髋关节OA患者（34例，年龄60+/-12岁，67%为女性）进行横断面研究。结果单样本t检验结果显示，左NAc体积显著低于正常值（t = -2.7368, df = 33， p值= 0.009）。在包含颅内总容积（TIV）、性别和年龄的模型（F(4,29) = 6.642, p < 0.001, R2 = 0.4781）中，以匹兹堡睡眠质量指数（PSQI）评估的睡眠质量（t = -3.416, p = 0.002）显著预测左NAc容积。睡眠效率（t = 2.362, p = 0.025），而非卧床时间（p > 0.05）也是显著的预测因子。在探索睡眠与性别相互作用的模型中，只有睡眠效率显示出了相互作用，这表明睡眠效率较差的女性左NAc体积更低（t = -2.086, p = 0.046，尽管在进行多重比较校正后并不显著，pFDR = 0.138）。结论NAc体积的减少作为疼痛的候选生物标志物可能受到睡眠的影响。这一在慢性髋关节炎人群中的探索性发现与之前仅在健康参与者的动物和实验性疼痛/睡眠研究中报道的结果一致。左侧NAc作为慢性疼痛的候选生物标志物对睡眠质量的影响很敏感，尤其是在OA女性患者中。

{"title":"Left nucleus accumbens volume is associated with poor sleep in hip osteoarthritis","authors":"Natalia Egorova-Brumley , Luiza Bonfim Pacheco , Gabby Knox , Leila Nategh , Fiona Dobson , Michelle Hall","doi":"10.1016/j.ynpai.2025.100203","DOIUrl":"10.1016/j.ynpai.2025.100203","url":null,"abstract":"<div><h3>Objective</h3><div>Reduction in the volume of the nucleus accumbens (NAc) has emerged as a promising signature of chronic pain transition, including in osteoarthritis (OA). Yet, less is known about the factors that could influence these changes in the mesolimbic system. Given that poor sleep is common in OA, and recent studies of sleep disturbance on pain perception in animals and healthy populations have specifically implicated the NAc, we hypothesised that the left NAc volume in hip OA would be associated with sleep quality and quantity. Furthermore, we explored how sex interacts with this relationship.</div></div><div><h3>Methods</h3><div>Cross-sectional study in participants with hip OA (n = 34; aged 60+/-12 years, 67 % females) who reported moderate pain were recruited.</div></div><div><h3>Results</h3><div>A one-sample <em>t</em>-test showed that the left NAc volumes were significantly lower than normative values (t = -2.7368, df = 33, p-value = 0.009). In a model (F(4, 29) = 6.642, p < 0.001, R2 = 0.4781) including the total intracranial volume (TIV), sex and age, the left NAc volume was significantly predicted by sleep quality (t = -3.416, p = 0.002) assessed with Pittsburgh Sleep Quality Index (PSQI). Sleep efficiency (t = 2.362, p = 0.025) but not hours spent in bed (p > 0.05) was also a significant predictor. With models exploring sleep*sex interactions, only sleep efficiency demonstrated an interaction, suggesting that the left NAc volume is lower in females with worse sleep efficiency (t = -2.086, p = 0.046, albeit not significant when corrected for multiple comparisons, pFDR = 0.138.)</div></div><div><h3>Conclusions</h3><div>Our results suggest that the reduction of the NAc volumes as a candidate biomarker of pain might be influenced by sleep. This exploratory finding in a chronic hip OA population is consistent with the results previously only reported in animal and experimental pain/sleep studies in healthy participants.</div></div><div><h3>Significance</h3><div>The left NAc as a candidate biomarker of chronic pain is sensitive to the effects of sleep quality, especially in females with OA.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"18 ","pages":"Article 100203"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145571069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Circulating microRNAs differentiate nociceptive and nociplastic pain: An exploratory study 循环microRNAs区分伤害性和伤害性疼痛：一项探索性研究

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 DOI: 10.1016/j.ynpai.2025.100191

Hiroyuki Nishie , Hideki Nakatsuka , Kazunori Iwasa , Yuka Sakuta , Yuichiro Toda , Shigeru Mitani , Takeshi Nagasaka

Background

Nociceptive and nociplastic pain arise from distinct biological mechanisms, yet their differentiation remains clinically challenging. Circulating microRNAs (miRNAs) are promising candidates for objective, mechanism-based pain classification.

Objective

To explore whether specific circulating miRNAs can differentiate nociceptive pain in patients with hip osteoarthritis (HO) from nociplastic pain in patients with chronic primary pain (CPP), and to assess their relationship with clinical and psychological outcomes.

Methods

In this exploratory, single-center study, plasma samples were collected from patients with HO (n = 13), CPP (n = 11), and healthy controls (n = 7). Microarray screening identified candidate miRNAs, which were validated via real-time PCR. Pain intensity (NRS), disability (PDAS), quality of life (EQ-5D), and psychological factors (PCS, PSEQ, TSK-11, PHQ-9) were assessed. Classification accuracy was evaluated using decision tree modeling and ROC analysis.

Results

Let-7a, miR-26a, and miR-16 showed distinct expression profiles and contributed to a predictive model with strong performance (R² = 0.677; AUC > 0.94). Let-7a expression was associated with structural joint changes in HO but not subjective pain ratings. MiR-26a correlated with cognitive-affective pain traits in CPP, and miR-16 decreased following CBT, suggesting a role in treatment-related neuroplasticity. MiR-126 and miR-146a were linked to reductions in pain intensity post-surgery in the HO group. QOL improved in HO, while psychological factors remained prominent in CPP.

Conclusions

This pilot study suggests that circulating miRNAs may aid in differentiating nociceptive and nociplastic pain mechanisms and tracking treatment effects. While preliminary, these findings support the potential utility of miRNA-based biomarkers in precision pain diagnostics and personalized management strategies.

背景：伤害性疼痛和伤害性疼痛产生于不同的生物学机制，但它们的区分在临床上仍然具有挑战性。循环microRNAs （miRNAs）是基于客观机制的疼痛分类的有希望的候选者。目的探讨特异性循环mirna是否能够区分髋关节骨关节炎（HO）患者的伤害性疼痛和慢性原发性疼痛（CPP）患者的伤害性疼痛，并评估它们与临床和心理结局的关系。方法在本探索性单中心研究中，收集HO患者（n = 13）、CPP患者（n = 11）和健康对照（n = 7）的血浆样本。微阵列筛选确定候选mirna，并通过实时PCR验证。评估疼痛强度（NRS）、残疾程度（PDAS）、生活质量（EQ-5D）和心理因素（PCS、PSEQ、TSK-11、PHQ-9）。采用决策树模型和ROC分析评估分类精度。结果slet -7a、miR-26a和miR-16表现出不同的表达谱，对预测模型有很强的作用(R2 = 0.677；AUC祝辞0.94)。Let-7a表达与HO的关节结构变化有关，但与主观疼痛评分无关。MiR-26a与CPP的认知-情感性疼痛特征相关，并且miR-16在CBT后下降，提示在治疗相关的神经可塑性中起作用。MiR-126和miR-146a与HO组术后疼痛强度的降低有关。HO患者的生活质量改善，而CPP患者的心理因素仍然突出。结论本初步研究表明，循环mirna可能有助于区分伤害性和伤害性疼痛机制，并追踪治疗效果。虽然是初步的，但这些发现支持了基于mirna的生物标志物在精确疼痛诊断和个性化管理策略中的潜在效用。

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引用次数: 0

FL/FLT3 signaling enhances mechanical pain hypersensitivity through Interleukin-1 beta (IL-1β) in male mice FL/FLT3信号通过白细胞介素-1β (IL-1β)增强雄性小鼠的机械性疼痛超敏反应

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 DOI: 10.1016/j.ynpai.2025.100202

Corinne Sonrier , Chamroen Sar , Ivo Melo , Lucie Dioufoulet , Gabriel V. Lucena-Silva , Sylvie Mallié , Juliette Bertin , Jean-Philippe Leyris , Fabrice Ango , Thiago M. Cunha , Hamid Moha ou Maati , Jean Valmier , Cyril Rivat , Ilana Méchaly

Fms-like tyrosine kinase 3 (FLT3) plays a critical role in chronic pain through its ligand FL, a cytokine that triggers mechanical pain hypersensitivity. However, the underlying molecular mechanisms remain unclear. Here, we investigate the potential interplay between FL and IL-1β a key cytokine in DRG neurons sensitization and mechanical hyperalgesia through both in vitro and in vivo approaches. ELISA assays reveal that intrathecal FL administration significantly increases IL-1β protein levels in both the DRG and dorsal spinal cord of mice, by four hours post-injection. Using video microscopy and [Ca²⁺] ₁ fluorescence imaging in primary DRG neuron cultures, we demonstrate that FL potentiation of TRPV1 receptor responses to capsaicin is partially mediated by IL-1β signalling, as evidenced by a significant reduction in this potentiation in the presence of the IL-1 receptor antagonist, IL-1Ra. Furthermore, FLT3-driven acute mechanical pain hypersensitivity in vivo is reduced both by prior administration of IL-1Ra and in IL-1 receptor knockout mice. Importantly, IL-1β-induced mechanical pain hypersensitivity remains independent of FLT3 signalling as shown in Flt3 knockout mice. Collectively our findings expand the understanding of neuro-immune interactions by demonstrating a potential functional link between FL/FLT3 and IL-1β/IL-1R signalling in nociceptive processing.

fms样酪氨酸激酶3 （FLT3）通过其配体FL在慢性疼痛中起关键作用，FL是一种触发机械性疼痛超敏反应的细胞因子。然而，潜在的分子机制尚不清楚。在这里，我们通过体外和体内两种方法研究了FL和IL-1β之间的潜在相互作用，IL-1β是DRG神经元致敏和机械性痛觉过敏的关键细胞因子。ELISA检测显示，鞘内给药4小时后，小鼠DRG和脊髓背段IL-1β蛋白水平均显著升高。使用视频显微镜和[Ca2+] 1荧光成像在原代DRG神经元培养中，我们证明了TRPV1受体对辣椒素反应的FL增强部分是由IL-1β信号介导的，IL-1受体拮抗剂IL-1Ra的存在显著降低了这种增强。此外，预先给药IL-1Ra和IL-1受体敲除小鼠可减少体内flt3驱动的急性机械性疼痛超敏反应。重要的是，在FLT3敲除小鼠中显示，il -1β诱导的机械性疼痛超敏反应仍然独立于FLT3信号传导。总的来说，我们的研究结果通过证明FL/FLT3和IL-1β/IL-1R信号在伤害性加工中的潜在功能联系，扩大了对神经免疫相互作用的理解。

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引用次数: 0

Glutamate levels in the cingulate cortex are associated with objective markers of pain sensitivity by way of pre-stimulus alpha band oscillations 扣带皮层中的谷氨酸水平通过刺激前α带振荡与疼痛敏感性的客观标记相关联

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 DOI: 10.1016/j.ynpai.2025.100204

Paulina S. Scheuren , Oscar Ortiz , Lukas D. Linde , Cassandra M. Choles , Erin L. MacMillan , John L.K. Kramer

Pain varies substantially from one individual to the next. Understanding the role of brain function in variations to pain, both in health and disease, represents an important steppingstone towards individualized pain management. This study aimed to investigate the association between glutamate levels and pain sensitivity, and whether this is mediated by alpha band oscillations. Fifty-one healthy individuals were recruited for this study. Laser evoked potentials (LEPs) and pain ratings were recorded in response to 20 stimuli applied at 4 different intensities (2.75, 3, 3.25, 3.5 J) to the right volar forearm. Brain alpha band oscillations (7–13 Hz) were extracted from the pre-stimulus timeframe (−1000 ms to −100 ms). Single-voxel magnetic resonance spectroscopy data were collected to estimate regional differences in glutamate levels across the anterior (ACC) and posterior cingulate cortex (PCC) using a 3 T scanner. Cluster analysis of LEPs revealed two clusters (high vs. low N2P2 amplitudes). Glutamate levels were reduced in the PCC versus ACC in the ‘low LEP’ (t = 3.6, p < 0.001), but not ‘high LEP’ cluster (t = 1.08, p = 0.285). Causal mediation analysis revealed that the effect of ACC:PCC glutamate ratio on LEP peak-to-peak amplitudes was mediated via pre-stimulus alpha band oscillations (β_indirect = −25.6(−63.9, −2.4), p = 0.034]. This study indicates that glutamate levels across the cingulate cortexshape subsequent brain responses to noxious input, and that this is mediated by pre-stimulus alpha band oscillations. Both brain metabolites and oscillations thus likely play a vital role in individual variabilities in experimental pain.

每个人的疼痛都有很大的不同。了解大脑功能在健康和疾病中疼痛变化中的作用，是实现个性化疼痛管理的重要基石。本研究旨在探讨谷氨酸水平与疼痛敏感性之间的关系，以及这种关系是否由α波段振荡介导。这项研究招募了51名健康个体。在4种不同强度（2.75、3、3.25、3.5 J）的20种刺激下，记录右掌侧前臂的激光诱发电位（LEPs）和疼痛评分。从刺激前时间框架（−1000 ms至−100 ms）中提取大脑α波段振荡（7-13 Hz）。收集单体素磁共振波谱数据，使用3t扫描仪估计前扣带皮层（ACC）和后扣带皮层（PCC）谷氨酸水平的区域差异。lep的聚类分析显示两个聚类（高和低N2P2振幅）。在“低LEP”组中，PCC组的谷氨酸水平比ACC组降低（t = 3.6, p < 0.001），但在“高LEP”组中没有（t = 1.08, p = 0.285）。因果中介分析表明，ACC:PCC谷氨酸比值对LEP峰间振幅的影响是通过刺激前α带振荡介导的（β间接= - 25.6(- 63.9,- 2.4),p = 0.034）。该研究表明，扣带皮层的谷氨酸水平决定了随后大脑对有害输入的反应，这是由刺激前α带振荡介导的。因此，脑代谢物和振荡可能在实验性疼痛的个体差异中起着至关重要的作用。

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引用次数: 0

Enhanced trafficking of an inherited erythromelalgia NaV1.7 mutant channel at a physiological temperature 生理温度下遗传性红斑性肢痛症NaV1.7突变通道的增强运输

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-06-18 DOI: 10.1016/j.ynpai.2025.100188

Malgorzata A. Mis , Sidharth Tyagi , Elizabeth J. Akin , Mohammad-Reza Ghovanloo , Peng Zhao , Fadia Dib-Hajj , Andrew D. Randall , Stephen G. Waxman , Sulayman D. Dib-Hajj

Gain-of-function mutations which enhance activation of Na_V1.7, a widely expressed sodium channel in nociceptors, cause human pain disorders including inherited erythromelalgia (IEM). IEM is characterized by attacks of burning pain in distal extremities triggered by warmth, with cooling of affected limbs providing temporary relief. We investigated the behaviour of the IEM-linked L858F mutant Na_V1.7 channel at physiological normal skin temperature (NST, 33–35 °C) in IB4-negative DRG sensory neurons known to include thermosensors. Using voltage-clamp recordings at NST we found that the Na_V1.7-L858F mutant channel shows the characteristic hyperpolarizing shift in activation as has been previously found in recordings at room temperature, and that the current density of the L858F channels is significantly larger than that of WT channels. Using a live-cell optical pulse-chase imaging methodology at NST we observed that accelerated forward-trafficking significantly increases membrane insertion of mutant channels in IB4^- neurons. Current-clamp recordings at NST show increased firing of IB4^- neurons that express the L858F mutant channel, consistent with increased trafficking of the channel at this physiological temperature. Our findings identify enhanced trafficking and membrane insertion of the L858F mutant channels at normal skin temperature in IB4^- neurons as an additional mechanism underlying IEM-related neuronal hyperexcitability.

NaV1.7是一种在痛觉感受器中广泛表达的钠通道，其功能获得性突变可增强NaV1.7的激活，导致包括遗传性红斑性肢痛症（IEM）在内的人类疼痛疾病。IEM的特征是由温暖引发的远端肢体灼痛发作，对受累肢体进行冷却可以暂时缓解疼痛。我们研究了iem连接的L858F突变体NaV1.7通道在生理正常皮肤温度下（NST, 33-35°C）在ib4阴性DRG感觉神经元中的行为，这些神经元已知包括热传感器。利用NST下的电压钳记录，我们发现NaV1.7-L858F突变通道在激活时表现出与之前在室温记录中发现的特征超极化位移，并且L858F通道的电流密度明显大于WT通道。利用NST的活细胞光脉冲追踪成像方法，我们观察到加速的前向运输显著增加了IB4-神经元突变通道的膜插入。NST下的电流钳记录显示，表达L858F突变通道的IB4-神经元的放电增加，与该生理温度下通道的运输增加一致。我们的研究发现，在正常皮肤温度下，IB4-神经元中L858F突变通道的运输和膜插入增强是iem相关神经元高兴奋性的另一个机制。

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