Neurobiology of Pain最新文献_第3页

Patient phenotyping for molecular profiling of neck and low back pain – Study protocol 颈部和腰痛分子谱的患者表型分析-研究方案

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 Epub Date: 2025-05-22 DOI: 10.1016/j.ynpai.2025.100186

Michele Curatolo , Cathryn Payne , Abby P. Chiu , Nguyen T. Tran , Natalie Yap , Christoph P. Hofstetter , Joseph B. Lesnak , Asta Arendt-Tranholm , Theodore J. Price , Jeffrey G. Jarvik , Judith A. Turner

Background

Chronic neck and low back pain are highly prevalent, leading causes of disability, and associated with long-term opioid use. The development of effective therapeutics is hampered by the limited understanding of the molecular mechanisms underlying these conditions. The Human Nociceptor and Spinal Cord Molecular Signature Center is a consortium within the NIH PRECISION Human Pain Network. The Center aims to fundamentally advance the understanding of the molecular neurobiology and neuroimmunology underlying human neck and low back pain, thereby enabling the discovery of therapeutic targets. We are pursuing this aim by applying bulk, single cell and spatial transcriptomics to tissues recovered from patients with neck and low back pain undergoing C1-2 and lumbar arthrodesis. The C2 dorsal root ganglion, facet joints, muscles, fascia, and intervertebral discs are harvested; control tissues are obtained from organ donors. A critical advantage of human research is the study of molecular neurobiological mechanisms in the context of the phenotypic complexity of chronic pain. The aim of this article is to summarize the rationale and methods used in our project to phenotype patients.

Methods

Phenotyping domains include pain-related characteristics such as pain intensity, duration, and location; physical function; psychosocial function; neuropathic components assessed by self-report and quantitative sensory testing; somatosensory functions such as mechanical pain sensitivity and temporal summation; and radiological findings.

Conclusion

We anticipate that comprehensive phenotyping will greatly facilitate the identification of phenotype-specific transcriptional signatures associated with chronic neck and low back pain, revealing new neurobiological and/or neuro-immunological mechanisms of painful diseases.

慢性颈部和下背部疼痛非常普遍，是致残的主要原因，并与长期使用阿片类药物有关。由于对这些疾病的分子机制了解有限，有效治疗方法的发展受到阻碍。人类伤害感受器和脊髓分子特征中心是美国国立卫生研究院精密人类疼痛网络的一个联盟。该中心旨在从根本上推进对人类颈部和腰痛的分子神经生物学和神经免疫学的理解，从而发现治疗靶点。我们正在通过将大体积、单细胞和空间转录组学应用于接受C1-2和腰椎关节融合术的颈部和腰痛患者恢复的组织来实现这一目标。切除C2背根神经节、小关节、肌肉、筋膜和椎间盘；对照组织来自器官捐献者。人类研究的一个关键优势是在慢性疼痛表型复杂性的背景下研究分子神经生物学机制。本文的目的是总结在我们的项目的基本原理和方法，以表型患者。方法分型域包括疼痛相关特征，如疼痛强度、持续时间和部位；生理功能;社会心理功能;用自我报告和定量感觉测试评估神经病变成分；躯体感觉功能，如机械疼痛敏感性和时间累加；还有放射检查结果。结论全面的表型分析将极大地促进慢性颈、腰痛相关表型特异性转录特征的识别，揭示疼痛性疾病的新的神经生物学和/或神经免疫学机制。

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引用次数: 0

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 Epub Date: 2025-10-08 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 Epub Date: 2025-11-13 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。

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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 : 2025-07-01 Epub 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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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 Epub Date: 2025-11-23 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

The RNA-binding protein CELF4 is a negative regulator of sensory neuron excitability and mechanical and heat behavioral sensitivity rna结合蛋白CELF4是感觉神经元兴奋性、机械和热行为敏感性的负调节因子

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 Epub Date: 2025-05-08 DOI: 10.1016/j.ynpai.2025.100184

Madison G. Mueth , Peter Neufeld , Merilla Michael , Aidan McGrath-Conwell , Eliza Grlickova-Duzevik , Tamara King , Christoph Straub , Benjamin J. Harrison

RNA-binding proteins (RBPs) regulate gene function by controlling RNA processing, transport, stability, and translation. Recent mechanistic and pre-clinical studies demonstrate that nociceptive sensitivity and plasticity are regulated by RNA-protein interactions. Investigating RBP function in sensory neurons may reveal new strategies to modulate nociceptor excitability and/or sensitivity and improve our understanding of mechanisms that contribute to pain chronification. We previously identified the RBP CUG triplet repeat binding protein (CUGBP) embryonic lethal abnormal vision (Elav)-like family member 4 (CELF4) as co-expressed with nociceptive markers in mouse, rat, and macaque dorsal root ganglia (DRG). In the central nervous system, CELF4 limits the translation of synaptic mRNAs, and loss of CELF4 results in hyperexcitability of excitatory neurons and spontaneous seizures. To elucidate the function of CELF4 in sensory neurons, we employed conditional knockout (KO) mouse models, with Celf4 deleted selectively in populations of adult DRG neurons. Using patch-clamp electrophysiology in acutely dissociated neurons, we observed a striking reduction in rheobase and hyperexcitability of capsaicin-sensitive adult Celf4 KO DRG neurons compared to controls. Behavioral assessments revealed that these mice display robust mechanical and thermal hypersensitivity and an exaggerated evoked hypersensitivity response to intraplantar capsaicin and nerve growth factor. These studies reveal that the translational regulator CELF4 is a powerful negative regulator of sensory neuron excitability and sensory thresholds to heat and mechanical stimuli resulting in thermal and mechanical hypersensitivity in uninjured mice and exacerbating hypersensitivity in injured mice. These findings elucidate a novel mechanism for modulating sensory neuron excitability with high specificity to putative nociceptors.

RNA结合蛋白（rbp）通过控制RNA加工、转运、稳定性和翻译来调节基因功能。最近的机制和临床前研究表明，伤害性敏感性和可塑性是由rna -蛋白相互作用调节的。研究RBP在感觉神经元中的功能可能揭示调节伤害感受器兴奋性和/或敏感性的新策略，并提高我们对疼痛慢性化机制的理解。我们之前在小鼠、大鼠和猕猴背根神经节（DRG）中发现了RBP CUG三联体重复结合蛋白（CUGBP）胚胎致死性异常视力（Elav）样家族成员4 （CELF4）与伤害性标志物共表达。在中枢神经系统中，CELF4限制了突触mrna的翻译，CELF4的缺失导致兴奋性神经元的高兴奋性和自发性癫痫发作。为了阐明CELF4在感觉神经元中的功能，我们采用了条件敲除（KO）小鼠模型，在成年DRG神经元群体中选择性地删除CELF4。利用膜片钳电生理学对急性解离神经元进行观察，我们发现与对照相比，辣椒素敏感的成人cellf4 KO DRG神经元的流变酶和高兴奋性显著降低。行为评估显示，这些小鼠表现出强烈的机械和热超敏反应，并对足底辣椒素和神经生长因子表现出夸大的诱发超敏反应。这些研究表明，翻译调节因子CELF4是一个强大的感觉神经元兴奋性和感觉阈值对热和机械刺激的负调节因子，导致未损伤小鼠的热和机械超敏反应，并加剧损伤小鼠的超敏反应。这些发现阐明了一种调节感觉神经元兴奋性的新机制，该机制对假定的伤害感受器具有高特异性。

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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 Epub Date: 2025-07-05 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

R and S enantiomers of CBD3063, a CaV2.2 N-type calcium channel modulator, alleviate capsaicin-induced inflammatory pain CaV2.2 n型钙通道调节剂CBD3063的R和S对映体可减轻辣椒素引起的炎症性疼痛

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 Epub Date: 2025-05-16 DOI: 10.1016/j.ynpai.2025.100185

Santiago Loya-López , Erick J. Rodríguez-Palma , Aida Calderón-Rivera , Kimberly Gomez , Samantha Perez-Miller , Rajesh Khanna

N-type voltage-gated calcium channels (Ca_V2.2) play a pivotal role in pain signaling, rendering them promising targets for pain treatment. However, direct blockers of Ca_V2.2 have demonstrated limited efficacy due to adverse side effects and inadequate blood–brain barrier penetration. In previous work, we developed CBD3063, a small molecule peptidomimetic that disrupts the Ca_V2.2-CRMP2 (collapsin response mediator protein 2) interaction, resulting in a reduction of Ca_V2.2 currents and pain relief without side effects. In this study, we investigated the individual contributions of the (R) and (S) enantiomers of CBD3063 to its pharmacological effects. Whole-cell patch-clamp recordings from mouse dorsal root ganglion (DRG) sensory neurons indicated that the (S) and (R) enantiomers reduced Ca_V2.2 currents. Furthermore, racemic CBD3063 and the (S) enantiomer exhibited antinociceptive effects in the capsaicin-induced model of inflammatory pain. These findings suggest that the (S) and (R) enantiomers contribute to the therapeutic effects of CBD3063.

n型电压门控钙通道（CaV2.2）在疼痛信号传导中起着关键作用，使其成为疼痛治疗的有希望的靶点。然而，由于副作用和血脑屏障穿透不足，CaV2.2的直接阻滞剂的疗效有限。在之前的工作中，我们开发了CBD3063，一种小分子拟肽，破坏CaV2.2- crmp2（塌陷反应介质蛋白2）的相互作用，导致CaV2.2电流减少和疼痛缓解，没有副作用。在这项研究中，我们研究了CBD3063的(R)和(S)对映体对其药理作用的单独贡献。来自小鼠背根神经节（DRG）感觉神经元的全细胞膜片钳记录显示(S)和(R)对映体降低了CaV2.2电流。此外，外消旋CBD3063和(S)对映体在辣椒素诱导的炎症性疼痛模型中表现出抗伤害性作用。这些发现表明(S)和(R)对映体有助于CBD3063的治疗效果。

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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 Epub Date: 2025-10-31 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

The contribution of clock genes BMAL1 and PER2 in osteoarthritis-associated pain 时钟基因BMAL1和PER2在骨关节炎相关疼痛中的作用。

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-01-01 Epub Date: 2024-12-22 DOI: 10.1016/j.ynpai.2024.100177

Erick J. Rodríguez-Palma , Santiago Loya-Lopez , Kyle Allen , Yenisel Cruz-Almeida , Rajesh Khanna

Joint pain is the primary symptom of osteoarthritis (OA) and the main motivator for patients to seek medical care. OA-related pain significantly restricts joint function and diminishes quality of life. Despite the availability of various pain-relieving medications for OA, current treatment strategies often fall short in delivering adequate pain relief. Furthermore, long-term use of pain medications for OA management is frequently linked with notable side effects and toxicities, suggesting the need to explore new potential targets to treat pain in OA patients. In this context, clock genes, particularly brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) and period circadian protein homolog 2 (PER2), known for their role in circadian rhythms, represent promising opportunities for pharmacological interventions due to their involvement in both the development and maintenance of OA pain. While BMAL1 and PER2 have been extensively studied in neuropathic and inflammatory pain, their specific contributions to OA pain remain less clear, demanding further investigation. This narrative review aims to synthesize the relationship between OA pain and the BMAL1 and PER2 signaling pathways, ultimately exploring the potential therapeutic role of clock genes in addressing this challenging condition.

关节疼痛是骨关节炎（OA）的主要症状，也是患者求医的主要动机。oa相关疼痛严重限制关节功能，降低生活质量。尽管有各种缓解OA疼痛的药物，但目前的治疗策略往往不能提供足够的疼痛缓解。此外，长期使用止痛药治疗骨性关节炎通常与显著的副作用和毒性有关，这表明有必要探索治疗骨性关节炎患者疼痛的新潜在靶点。在这种情况下，时钟基因，特别是脑和肌肉芳烃受体核易位样1 （BMAL1）和周期昼夜节律蛋白同源物2 (PER2)，因其在昼夜节律中的作用而闻名，由于它们参与OA疼痛的发展和维持，为药物干预提供了有希望的机会。虽然BMAL1和PER2在神经性疼痛和炎症性疼痛中得到了广泛的研究，但它们在OA疼痛中的具体作用尚不清楚，需要进一步研究。本综述旨在综合OA疼痛与BMAL1和PER2信号通路之间的关系，最终探索时钟基因在解决这一具有挑战性的疾病中的潜在治疗作用。

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引用次数: 0