Neurobiology of Pain最新文献

Differential Cortico-Thalamic reorganization in Opioid-Induced hyperalgesia and neuropathic pain male rats 阿片类药物致痛觉过敏和神经性疼痛雄性大鼠皮质-丘脑的差异重组

Q2 Medicine

Neurobiology of Pain

Pub Date : 2026-01-01 Epub Date: 2025-12-25 DOI: 10.1016/j.ynpai.2025.100206

Aoling Cai , Qing Liu , Wenchang Zhou , Danhao Zheng , Wen Zhang , Xiaodong Liu , Mamatmusayeva Nilufar , Anne Manyande , Feng Gao , Jie Wang , Jun Fang , Xuebi Tian

Both opioid use and peripheral nerve injury can lead to hyperalgesia. Whereas in peripheral nerve injury, the central neuroplastic is secondary to sustained peripheral signaling, opioid-induced hyperalgesia (OIH) involves maladaptive alterations in both the peripheral and central nervous systems. However, the precise neurobiological mechanisms underlying these two distinct forms of hyperalgesia remain incompletely understood. In this study, OIH and spared nerve injury (SNI), a model of peripheral nerve injury, were established in male rats to investigate the similarities and differences in brain activity. Resting-state fMRI and mechanical stimulus task-state fMRI were employed to identify the differential brain regions between those two groups. Both resting-state fMRI and task-state fMRI revealed substantial differences in pain-related functional networks between these two models. Notably, OIH was characterized by a widespread reduction in whole-brain activity, whereas SNI primarily exhibited abnormal activation in specific pain-processing regions. Specifically, enhanced synchrony between the medial parietal association cortex (MPtA) and the ventral posterior thalamic nucleus (VP) was observed in the OIH model, but not in the SNI model. These abnormal changes were further confirmed through in vivo electrophysiological recordings. This study reveals a whole-brain activity responses to resting state and mechanical stimuli in both OIH and SNI models, while also identifying a special thalamo-parietal circuit involved in opioid-induced hyperalgesia. It provides new insights into the neural mechanisms between OIH and SNI, potentially guiding the new strategies for hyperalgesia therapy.

阿片类药物使用和周围神经损伤均可导致痛觉过敏。而在周围神经损伤中，中枢神经可塑性是继发于持续的外周信号，阿片诱导的痛觉过敏（OIH）涉及外周和中枢神经系统的不适应改变。然而，这两种不同形式的痛觉过敏背后的确切神经生物学机制仍然不完全清楚。本研究在雄性大鼠中建立OIH和周围神经损伤模型SNI，探讨脑活动的异同。利用静息状态功能磁共振成像和机械刺激任务状态功能磁共振成像来识别两组大脑区域的差异。静息状态功能磁共振成像和任务状态功能磁共振成像显示，这两种模型在疼痛相关功能网络上存在实质性差异。值得注意的是，OIH的特征是全脑活动的广泛减少，而SNI主要表现为特定疼痛处理区域的异常激活。具体来说，在OIH模型中观察到内侧顶叶联合皮层（MPtA）和丘脑后腹核（VP）之间的同步增强，而在SNI模型中没有。这些异常变化通过体内电生理记录进一步证实。本研究揭示了OIH和SNI模型对静息状态和机械刺激的全脑活动反应，同时也发现了一个特殊的丘脑-顶叶回路参与阿片类药物诱导的痛觉过敏。它为OIH和SNI之间的神经机制提供了新的见解，可能指导痛觉过敏治疗的新策略。

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引用次数: 0

Females show enhanced susceptibility to develop nerve injury and constant joint pain compared to males in a mouse model of knee joint pain 在小鼠膝关节疼痛模型中，与雄性相比，雌性对神经损伤和持续关节疼痛的易感性增强

Q2 Medicine

Neurobiology of Pain

Pub Date : 2026-01-01 Epub Date: 2026-02-06 DOI: 10.1016/j.ynpai.2026.100209

Madison G. Mueth , Abigail Del Greco , Tyler Vesey , Sebastien Sannajust , Victoria Eaton , Peter Caradonna , Talia Lizotte , Kathleen A. Becker , Eliza Grlickova-Duzevik , Benjamin J. Harrison , Tamara King

Arthritis is a leading cause of diminished quality of life from chronic pain and disability and is more severe in female patients. Arthritis pain is difficult to manage due to its heterogeneous nature. Patients report joint pain during use that dissipates with joint rest, however some patients also report constant joint pain that fails to abate with rest. A murine model of osteoarthritis knee joint pain was used to explore the hypothesis that constant joint pain is associated with increased nerve injury, and females develop constant pain and nerve injury at earlier stages of joint damage compared to males. Monosodium iodoacetate (MIA) was injected into the intra-articular space of the knee joint followed by analysis of weight asymmetry and analgesia-induced conditioned place preference (CPP) 2 weeks later. Knee joints and dorsal root ganglia (DRG) were collected following behavioral analyses to assess joint pathology, changes in innervation, and nerve injury. Females developed analgesia-induced CPP at a 5-fold lower concentration of MIA (16 mg/mL) compared to males (80 mg/mL), while males treated with 16 mg/mL MIA only developed weight asymmetry. Equivalent joint pathology and changes in innervation were observed in males and females treated with 16 mg/mL MIA despite differences in pain-like behaviors. Increased expression of activating transcription factor-3 (ATF3) mRNA, a marker of nerve injury, was only observed in DRG L2-L5 of females and males with analgesia-induced CPP. These observations indicate that females have increased susceptibility to arthritis associated nerve injury that likely contributes to sex differences in joint pain.

关节炎是慢性疼痛和残疾导致生活质量下降的主要原因，在女性患者中更为严重。由于其异质性，关节炎疼痛难以控制。患者报告使用期间的关节疼痛，随着关节休息而消失，然而一些患者也报告持续的关节疼痛，不能随着休息而减轻。研究人员使用小鼠骨关节炎膝关节疼痛模型来探索持续关节疼痛与神经损伤增加相关的假设，并且与男性相比，女性在关节损伤的早期阶段出现持续疼痛和神经损伤。将碘乙酸钠（Monosodium iodoacetate， MIA）注射于膝关节关节内间隙，2周后分析体重不对称和镇痛诱导的条件性位置偏好（CPP）。行为分析后采集膝关节和背根神经节（DRG），评估关节病理、神经支配变化和神经损伤。MIA浓度（16 mg/mL）为雄性（80 mg/mL）的5倍，雌性（16 mg/mL）出现了镇痛性CPP，而MIA浓度为16 mg/mL的雄性只出现了体重不对称。在16 mg/mL MIA治疗的男性和女性中，观察到相同的关节病理和神经支配的变化，尽管疼痛样行为存在差异。神经损伤标志物激活转录因子-3 (ATF3) mRNA表达升高，仅在镇痛性CPP女性和男性的DRG L2-L5中观察到。这些观察结果表明，女性对关节炎相关神经损伤的易感性增加，这可能导致关节疼痛的性别差异。

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引用次数: 0

Peripheral immune response and axonal degeneration in the hind paw skin of mice with experimental autoimmune encephalomyelitis 实验性自身免疫性脑脊髓炎小鼠后爪皮肤外周免疫应答和轴突变性

Q2 Medicine

Neurobiology of Pain

Pub Date : 2026-01-01 Epub Date: 2025-12-31 DOI: 10.1016/j.ynpai.2025.100207

Andrea G. Klassen , Timothy N. Friedman , Gustavo Tenorio , Jason R. Plemel , Anna M.W. Taylor , Bradley J. Kerr

Multiple sclerosis (MS) is traditionally considered a central nervous system (CNS) disease characterized by chronic inflammation and demyelination in the brain and spinal cord, often resulting in debilitating neuropathic pain. While the primary mechanisms of pain in MS are attributed to central mechanisms, recent evidence suggests that peripheral nervous system (PNS) changes may also contribute. Peripheral neurons in the dorsal root ganglia (DRG), which relay sensory information to the CNS, can undergo inflammation-induced structural and functional changes that amplify pain sensitivity. In human MS and its animal model, experimental autoimmune encephalomyelitis (EAE), inflammation and neuronal injury have been observed in the DRG, yet the role of the PNS in MS pain remains underexplored. To investigate peripheral contributions to pain in EAE, we examined disease-induced changes in hind paw cutaneous tissue and found increased inflammation at disease onset that coincided with tactile hypersensitivity. Intraepidermal nerve fiber (IENF) loss was observed in both sexes at disease onset; however, a sex-specific difference in reinnervation emerged by four weeks post-immunization, with females exhibiting significant reinnervation while males did not. These findings identify sex-dependent patterns of peripheral innervation during EAE and raise the possibility that peripheral mechanisms may contribute differently across sexes.

多发性硬化症（MS）传统上被认为是一种以脑和脊髓慢性炎症和脱髓鞘为特征的中枢神经系统（CNS）疾病，通常导致衰弱性神经性疼痛。虽然MS疼痛的主要机制归因于中枢机制，但最近的证据表明外周神经系统（PNS）的改变也可能起作用。背根神经节（DRG）中的外周神经元将感觉信息传递给中枢神经系统，可以经历炎症诱导的结构和功能变化，从而增强疼痛敏感性。在人类MS及其动物模型中，在DRG中观察到实验性自身免疫性脑脊髓炎（EAE）、炎症和神经元损伤，但PNS在MS疼痛中的作用尚不清楚。为了研究外周对EAE疼痛的影响，我们检查了疾病引起的后爪皮肤组织的变化，发现疾病发作时炎症增加与触觉过敏相一致。在发病时，两性均观察到表皮内神经纤维（IENF）丢失；然而，在免疫后四周，出现了性别特异性的神经再生差异，女性表现出显著的神经再生，而男性则没有。这些发现确定了脑电刺激过程中外周神经支配的性别依赖模式，并提出了外周机制可能在性别之间发挥不同作用的可能性。

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引用次数: 0

Xpro®1595 alleviates neuropathic pain by targeting spinal dorsal horn ADAM17-mediated inflammation Xpro®1595通过靶向脊髓背角adam17介导的炎症减轻神经性疼痛。

Q2 Medicine

Neurobiology of Pain

Pub Date : 2026-01-01 Epub Date: 2026-02-12 DOI: 10.1016/j.ynpai.2026.100210

Li Li , Yidie Su , Ling-ling Sun , Wei-Wei Yao , Yan-Yan Sun

A disintegrin and metalloprotease 17 (ADAM17) mediates the shedding of key pro-inflammatory cytokines, yet its specific contribution to neuropathic pain remains elusive. Here, we investigated the role of ADAM17 in the rat spinal nerve ligation (SNL) model. Following nerve injury, ADAM17 expression was significantly upregulated in the spinal dorsal horn (SDH) and dorsal root ganglion (DRG). Specifically, ADAM17 colocalized with TRPV1 and IB4 positive afferents in the superficial SDH, and with IB4, CGRP, and TRPV1 positive neurons in the DRG. Intrathecal administration of exogenous ADAM17 to naive rats recapitulated neuropathic pain behaviors—inducing mechanical and thermal hypersensitivity—and significantly increased the levels of TNF-α, IL-1β, and IL-6 in the SDH. Conversely, therapeutic treatment with Xpro®1595 markedly attenuated SNL-induced pain behaviors. This analgesic effect correlated with the suppression of injury-induced ADAM17 upregulation and a consequent reduction in proinflammatory cytokines. These findings demonstrate that ADAM17 is a critical driver of the neuroinflammatory cascade in neuropathic pain. Moreover, our data suggest that the analgesic efficacy of Xpro®1595 is mediated, at least in part, by disrupting this ADAM17-dependent inflammatory feedback loop.

崩解素和金属蛋白酶17 （ADAM17）介导关键促炎细胞因子的脱落，但其在神经性疼痛中的具体作用尚不明确。在此，我们研究了ADAM17在大鼠脊神经结扎（SNL）模型中的作用。神经损伤后，ADAM17在脊髓背角（SDH）和背根神经节（DRG）中的表达显著上调。具体而言，ADAM17与浅表SDH中的TRPV1和IB4阳性传入神经以及DRG中的IB4、CGRP和TRPV1阳性神经元共定位。鞘内给药外源性ADAM17会重现幼年大鼠的神经性疼痛行为，引起机械和热超敏反应，并显著增加SDH中TNF-α、IL-1β和IL-6的水平。相反，Xpro®1595治疗显著减轻snl引起的疼痛行为。这种镇痛作用与抑制损伤诱导的ADAM17上调和随后的促炎细胞因子减少有关。这些发现表明，ADAM17是神经性疼痛中神经炎症级联的关键驱动因素。此外，我们的数据表明，Xpro®1595的镇痛效果至少部分是通过破坏这种adam17依赖性炎症反馈循环来介导的。

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引用次数: 0

Context dependent roles of FGF13B-NaV1.7 interaction in pain signaling FGF13B-NaV1.7相互作用在疼痛信号传导中的上下文依赖作用

Q2 Medicine

Neurobiology of Pain

Pub Date : 2026-01-01 Epub Date: 2026-02-04 DOI: 10.1016/j.ynpai.2026.100208

Erick J. Rodríguez-Palma , Samantha Perez-Miller , Kimberly Gomez , Rajesh Khanna

Voltage-gated sodium channels, such as Na_V1.7, serve as pivotal regulators of sensory neuron excitability and nociception. While gain- and loss-of-function mutations in SCN9A cause inherited pain syndromes or congenital insensitivity to pain, the functional regulation of Na_V1.7channels by intracellular protein partners remains incompletely defined. Among these, the fibroblast growth factor 13 isoform B (FGF13B) has emerged as a critical, yet controversial, modulator of Na_V1.7. FGF13B binds the Na_V1.7C-terminal domain, but reported consequences of this interaction appear conflicting, with studies describing both suppression and enhancement of channel function and nociceptor excitability. Here, we review recent genetic, electrophysiological, and pharmacology advances and propose that FGF13B functions as a context-dependent regulatory rheostat of Na_V1.7 rather than as a unidirectional modulator. We highlight how the net functional outcome of this interaction depends on cellular and signaling context and discuss the therapeutic potential of targeting the FGF13B/Na_V1.7complex in pain conditions.

电压门控钠通道，如NaV1.7，是感觉神经元兴奋性和伤害性的关键调节因子。虽然SCN9A的功能获得和功能丧失突变导致遗传性疼痛综合征或先天性疼痛不敏感，但细胞内蛋白伴侣对nav1.7通道的功能调节仍不完全明确。其中，成纤维细胞生长因子13异构体B （FGF13B）已成为NaV1.7的关键但有争议的调节剂。FGF13B结合nav1.7 c末端结构域，但报道的这种相互作用的结果似乎相互矛盾，研究描述了通道功能和伤害感受器兴奋性的抑制和增强。在这里，我们回顾了最近的遗传学、电生理学和药理学进展，并提出FGF13B作为NaV1.7的上下文依赖性调节变阻器而不是单向调节剂。我们强调了这种相互作用的净功能结果如何取决于细胞和信号环境，并讨论了靶向FGF13B/ nav1.7复合物在疼痛条件下的治疗潜力。

{"title":"Context dependent roles of FGF13B-NaV1.7 interaction in pain signaling","authors":"Erick J. Rodríguez-Palma , Samantha Perez-Miller , Kimberly Gomez , Rajesh Khanna","doi":"10.1016/j.ynpai.2026.100208","DOIUrl":"10.1016/j.ynpai.2026.100208","url":null,"abstract":"<div><div>Voltage-gated sodium channels, such as Na<sub>V</sub>1.7, serve as pivotal regulators of sensory neuron excitability and nociception. While gain- and loss-of-function mutations in <em>SCN9A</em> cause inherited pain syndromes or congenital insensitivity to pain, the functional regulation of Na<sub>V</sub>1.7channels by intracellular protein partners remains incompletely defined. Among these, the fibroblast growth factor 13 isoform B (FGF13B) has emerged as a critical, yet controversial, modulator of Na<sub>V</sub>1.7. FGF13B binds the Na<sub>V</sub>1.7C-terminal domain, but reported consequences of this interaction appear conflicting, with studies describing both suppression and enhancement of channel function and nociceptor excitability. Here, we review recent genetic, electrophysiological, and pharmacology advances and propose that FGF13B functions as a context-dependent regulatory rheostat of Na<sub>V</sub>1.7 rather than as a unidirectional modulator. We highlight how the net functional outcome of this interaction depends on cellular and signaling context and discuss the therapeutic potential of targeting the FGF13B/Na<sub>V</sub>1.7complex in pain conditions.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"19 ","pages":"Article 100208"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189230","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

NGF stimulation alters the transcriptome and surface TrkB expression in axons of dorsal root ganglion neurons. NGF刺激改变背根神经节神经元轴突的转录组和表面TrkB表达。

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-08-05 eCollection Date: 2025-07-01 DOI: 10.1016/j.ynpai.2025.100194

Maximilian Koch, Manas Kshirsagar, Ankita Rawat, Abdolhossein Zare, Felicitas Schlott, Thorsten Bischler, Panagiota Arampatzi, Michael Briese, Michael Sendtner

Nerve growth factor (NGF) is released after injury from macrophages and other cell types and induces an inflammatory response in neurons, characterized by local subcellular reactions and transcriptomic modulation. NGF-induced axonal transcriptome modulation may be crucial for pain initiation and maintenance. To explore these acute modulations, we cultured dorsal root ganglion neurons in microfluidic chambers and stimulated the axons with NGF. We found that axonal levels of the Il7 transcript encoding interleukin-7 (IL-7) are increased after NGF stimulation, followed by IL-7 release from axons. In growth cones of sensory neurons, we also observed a reorganization of the ribosomal subunits 60S and 40S in response to NGF stimulation. In addition, a dynamic change in the spatio-temporal distribution of the Tropomyosin Kinase B (TrkB) receptor occurs at the plasma membrane of sensory neuron growth cones. TrkB is recruited from the endoplasmic reticulum (ER) leading to increased cell surface levels. De-novo synthesis of TrkB seems to be limited to somatic regions of sensory neurons. Thus, cytosolic mechanisms within distal regions of the sensory neurons may autonomously regulate signaling and translation in response to external NGF stimuli.

神经生长因子（NGF）在巨噬细胞和其他细胞损伤后释放，在神经元中诱导炎症反应，其特征是局部亚细胞反应和转录组调节。ngf诱导的轴突转录组调节可能对疼痛的发生和维持至关重要。为了探索这些急性调节，我们在微流控室中培养背根神经节神经元，并用NGF刺激轴突。我们发现，在NGF刺激后，编码白介素-7 （IL-7）的IL-7转录物的轴突水平增加，随后IL-7从轴突释放。在感觉神经元的生长锥中，我们还观察到核糖体亚基60S和40S在NGF刺激下的重组。此外，原肌球蛋白激酶B （TrkB）受体在感觉神经元生长锥质膜上的时空分布发生动态变化。TrkB从内质网（ER）募集，导致细胞表面水平升高。TrkB的De-novo合成似乎仅限于感觉神经元的体细胞区域。因此，感觉神经元远端区域内的细胞质机制可能在响应外部NGF刺激时自主调节信号传导和翻译。

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引用次数: 0

ASIC1a-associated mechanical hypersensitivity in the GlaKO Fabry disease mouse model GlaKO法布里病小鼠模型中asic1a相关的机械超敏反应

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 Epub Date: 2025-06-26 DOI: 10.1016/j.ynpai.2025.100189

Mayra Micaela Montes , Libia Catalina Salinas Castellanos , Georgina Oriana Mingolo Malnati , Juan Santiago Guidobono , Ariel Félix Gualtieri , Mariela Lacave , Romina De Lucca , María Natalia Gobetto , Pablo Gabriel Vetta , Zaira Soledad Verónica Náguila , Fernanda Toledo , Osvaldo Daniel Uchitel , Carina Weissmann

Different lines of evidence point to a role for Acid-sensing ion channel 1 (ASIC1) in pain perception, acting as sensors in both the central nervous system and peripheral tissues. While elevated ASIC1 protein expression has been documented in various pain conditions, our study focuses on its involvement in the context of Fabry disease (FD).

Using a mouse model of FD, we observed a significant increase in ASIC1 protein expression in pain-related areas including the anterior cingulate cortex (ACC), as well as the spinal cord (SC) and dorsal root ganglia (DRG) at the lumbar, thoracic, and cervical levels. This upregulation was accompanied by increased ASIC1a mRNA levels and ERK phosphorylation. Moreover, in FD mice, ASIC1 protein expression was found to be modulated by age and sex: it was higher in female mice than in males, and increased with age in both sexes.

These findings, together with our previous work showing unaltered ASIC1a mRNA levels but microRNA-mediated regulation of ASIC1a protein in the formalin-induced acute pain model, highlight distinct mechanisms of ASIC1a regulation in FD-associated versus acute pain. Additionally, our study revealed heightened mechanical sensitivity in FD mice that could be prevented using a channel blocker, further highlighting the involvement of ASIC1a channels in pain pathways associated with Fabry disease. Our findings suggest that ASIC1a channels may serve as promising therapeutic targets for pain management in Fabry disease.

不同的证据表明酸感离子通道1 （ASIC1）在疼痛感知中起作用，在中枢神经系统和外周组织中都起传感器的作用。虽然ASIC1蛋白表达升高已被记录在各种疼痛状况中，但我们的研究重点是它与法布里病（FD）的关系。通过小鼠FD模型，我们观察到ASIC1蛋白在疼痛相关区域的表达显著增加，包括前扣带皮层（ACC），以及腰椎、胸椎和颈椎水平的脊髓（SC）和背根神经节（DRG）。这种上调伴随着ASIC1a mRNA水平和ERK磷酸化的增加。此外，在FD小鼠中，发现ASIC1蛋白的表达受年龄和性别的调节：雌性小鼠的ASIC1蛋白表达高于雄性，并且随着年龄的增长，雌雄小鼠的ASIC1蛋白表达均增加。这些发现，加上我们之前的工作显示ASIC1a mRNA水平不变，但在福尔马林诱导的急性疼痛模型中，ASIC1a蛋白的microrna介导调节，突出了ASIC1a在fd相关和急性疼痛中的不同调节机制。此外，我们的研究显示，FD小鼠的机械敏感性升高可以通过通道阻滞剂来预防，进一步强调了ASIC1a通道参与与Fabry病相关的疼痛通路。我们的研究结果表明ASIC1a通道可能作为Fabry病疼痛管理的有希望的治疗靶点。

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引用次数: 0

A non-toxic analgesic elicits cell-specific genomic and epigenomic modulation by targeting the PAG brain region 一种无毒镇痛药通过靶向PAG脑区引发细胞特异性基因组和表观基因组调节

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 Epub Date: 2025-07-20 DOI: 10.1016/j.ynpai.2025.100192

Hernan A. Bazan , Brian L. Giles , Surjyadipta Bhattacharjee , Scott Edwards , Nicolas G. Bazan

Acetaminophen (ApAP) is widely used for pain management, but overuse or overdose leads to hepatotoxicity, making it the leading cause of acute liver failure globally. There is an urgent need for safer pain medications, as other non-opioid analgesics like non-steroidal anti-inflammatory drugs (NSAIDs) are nephrotoxic. We have identified SRP-001 as a safer, non-hepatotoxic, novel analgesic that overcomes ApAP’s limitations by avoiding NAPQI formation and preserving hepatic tight junctions. Using coupled RNA and ATAC sequencing, from the periaqueductal gray (PAG) midbrain region, we compared the genetic and epigenetic signatures of SRP-001 and ApAP treatments following complete Freund’s adjuvant (CFA)-induced inflammatory pain against no treatment and vehicle controls. Our analysis revealed differential activity in three transcription factor families (SOX, SP/KLF, and AP-1) with cell-specific patterns and altered neuron-neuron interactions through neurexin-neuregulin signaling. SRP-001 and ApAP demonstrated similar genetic and epigenetic outcomes, indicating that SRP-001 is a favorable alternative due to its non-hepatotoxic properties while maintaining the same antinociceptive effects as ApAP.

对乙酰氨基酚（ApAP）被广泛用于疼痛治疗，但过度使用或过量使用会导致肝毒性，使其成为全球急性肝衰竭的主要原因。由于其他非阿片类镇痛药如非甾体抗炎药（NSAIDs）具有肾毒性，因此迫切需要更安全的止痛药。我们已经确定SRP-001是一种更安全，无肝毒性的新型镇痛药，通过避免NAPQI的形成和保持肝紧密连接来克服ApAP的局限性。利用来自输水管周围灰质（PAG）中脑区域的RNA和ATAC偶联测序，我们比较了完全弗氏佐剂（CFA）诱导的炎症性疼痛与未治疗和对照对照相比，SRP-001和ApAP治疗的遗传和表观遗传特征。我们的分析揭示了三个转录因子家族（SOX、SP/KLF和AP-1）在细胞特异性模式下的差异活性，以及通过神经素-神经调节蛋白信号传导改变的神经元-神经元相互作用。SRP-001和ApAP表现出相似的遗传和表观遗传结果，表明SRP-001是一种良好的替代品，因为它具有非肝毒性，同时保持与ApAP相同的抗伤害性作用。

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引用次数: 0

Physiological actions of a humanized P2X4 scFv on peripheral and central neurons in male mice with neuropathic pain 人源化P2X4 scFv对神经性疼痛雄性小鼠外周和中枢神经元的生理作用

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 Epub Date: 2025-09-17 DOI: 10.1016/j.ynpai.2025.100198

Sachin Goyal , Ian Adams , Marena Montera , Nesia A. Zurek , Shivali Goyal , Adinarayana Kunamneni , Karin N. Westlund , Sascha R.A. Alles

Neuropathic pain remains a challenging clinical condition due to its resistance to conventional analgesics. The purinergic P2X4 receptor (P2X4R), an ATP-gated ion channel, is upregulated in sensory neurons and glial cells following nerve injury and is pivotal in chronic pain pathogenesis. This study evaluates the therapeutic potential of a novel humanized single-chain variable fragment antibody (hP2X4R scFv) targeting P2X4R in male mice models of neuropathic pain. Using spared nerve injury (SNI) and foramen rotundum inflammatory compression of the trigeminal infraorbital nerve (FRICT-ION) models, we demonstrate that a single intraperitoneal dose of hP2X4R scFv significantly reverses mechanical hypersensitivity for up to four weeks. Electrophysiological recordings from FosTRAP mice revealed that hP2X4R scFv reduced the excitability of Fos+ neurons in the spinal dorsal horn and ventrolateral periaqueductal gray (vlPAG), key regions involved in pain processing. In vitro, patch-clamp studies further showed that hP2X4R scFv selectively decreased action potential firing in larger diameter dorsal root ganglion (DRG) and trigeminal ganglion (TG) neurons from SNI and FRICT-ION mice, respectively, without affecting naïve neurons. These findings suggest that hP2X4R scFv modulates both central and peripheral neuronal excitability associated with chronic pain. The specificity and long-lasting efficacy of hP2X4R scFv highlights its promise as a non-opioid therapeutic candidate for neuropathic pain management.

神经性疼痛仍然是一个具有挑战性的临床条件，由于其抵抗传统的镇痛药。嘌呤能P2X4受体（P2X4R）是一种atp门控离子通道，在神经损伤后感觉神经元和胶质细胞中表达上调，在慢性疼痛发病中起关键作用。本研究评估了一种针对P2X4R的新型人源化单链可变片段抗体（hP2X4R scFv）在雄性小鼠神经性疼痛模型中的治疗潜力。通过使用余留神经损伤（SNI）和圆形孔炎性压迫三叉眶下神经（FRICT-ION）模型，我们证明单次腹腔注射hP2X4R scFv可显著逆转机械超敏反应长达四周。来自FosTRAP小鼠的电生理记录显示，hP2X4R scFv降低了脊髓背角和腹外侧导水管周围灰质（vlPAG）的Fos+神经元的兴奋性，这是参与疼痛加工的关键区域。体外膜片钳研究进一步表明，hP2X4R scFv分别选择性地降低SNI和FRICT-ION小鼠大直径背根神经节（DRG）和三叉神经节（TG）神经元的动作电位放电，而不影响naïve神经元。这些发现表明，hP2X4R scFv调节与慢性疼痛相关的中枢和外周神经元兴奋性。hP2X4R scFv的特异性和持久疗效突出了其作为神经性疼痛治疗的非阿片类药物候选药物的前景。

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引用次数: 0

The effect of depression on the peak alpha frequency as a biomarker of pain sensitivity 抑郁对作为疼痛敏感性生物标志物的α峰频率的影响

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 Epub Date: 2025-08-06 DOI: 10.1016/j.ynpai.2025.100193

Mingge Shi , Luiza Bonfim Pacheco , Natalia Egorova-Brumley

Objective

To assess how Peak Alpha Frequency (PAF) as a neurophysiological biomarker of pain sensitivity is influenced by conditions often comorbid with chronic pain, e.g., depression, and how methodological differences in deriving PAF, e.g., from Eyes-open (EO) vs. Eyes-closed (EC) EEG recordings affect this association.

Methods

We analyzed data from 47 participants (70 % female) aged 18–51 years (M = 25.0, SD = 6.50). Among them, all participants underwent EO EEG recording but only a subset of 25 participants underwent both EO and EC recording. Depression (Patient Health Quotient – 9 M = 4.49, SD = 3.96) and sensitivity to heat pain were measured.

Results

In EO, Spearman correlations showed no significant PAF-pain relationship (p = 0.530) but a positive correlation with depression (ρ = 0.348, p = 0.019). In EC, no significant correlations emerged, though a trend (p = 0.052) suggested depression might moderate PAF-pain links. Notably, the EO-EC PAF difference negatively correlated with depression (ρ = −0.54, p < 0.01).

Conclusions

PAF may be sensitive to depression, albeit in the opposite direction to pain, and therefore mask the association between PAF and pain in individuals with depression. Differences in EO vs. EC PAF, as well as the EO-EC difference warrant further study.

Significance

Depression affects PAF especially in the eyes-open recordings.

目的评估阿尔法峰频率（PAF）作为疼痛敏感性的神经生理生物标志物如何受到慢性疼痛共病（如抑郁症）的影响，以及从睁眼（EO）和闭眼（EC）脑电图记录中提取PAF的方法差异如何影响这种关联。方法对47例18 ~ 51岁（M = 25.0, SD = 6.50）参与者的资料进行分析，其中女性占70%。其中，所有参与者均进行了EO EEG记录，但只有25名参与者同时进行了EO和EC记录。抑郁（患者健康商- 9 M = 4.49, SD = 3.96）和对热痛的敏感性。结果在EO中，Spearman相关性显示paf与疼痛无显著相关性（p = 0.530），与抑郁呈正相关（ρ = 0.348, p = 0.019）。在EC中，没有显著的相关性出现，尽管趋势（p = 0.052）表明抑郁可能会缓和paf -疼痛的联系。EO-EC PAF差异与抑郁呈负相关(ρ = - 0.54, p <；0.01)。结论PAF可能对抑郁敏感，但与疼痛敏感方向相反，因此掩盖了抑郁症患者PAF与疼痛的关系。EO与EC的PAF差异，以及EO-EC的差异值得进一步研究。抑郁症影响PAF，特别是在睁眼记录中。

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