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 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

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 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

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

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 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

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 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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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 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

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 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 impact of nerve injury on the immune system across the lifespan is sexually dimorphic 神经损伤对免疫系统的影响在整个生命周期中是两性二态的

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 DOI: 10.1016/j.ynpai.2025.100195

Wen Bo S. Zhou , Xiang Q. Shi , Alain P. Zhang , Magali Millecamps , Jeffrey S. Mogil , Ji Zhang

Although nerve injury-associated neuroinflammation contributes to neuropathic pain, the long-term impact of such injury on systemic homeostasis and its potential role in pain remains elusive. In this study, we aim to understand the systemic changes that are present alongside chronic pain in nerve-injured male and female mice across their lifespan. We monitored mechanical and cold sensitivity in male and female mice starting at the age of 3–4 months old when they received spared nerve injury (SNI), up to 20-month post-injury. Alongside, we collected blood samples to track changes in immune cells with flow cytometry, and to assess inflammation-related serum proteome using a 111-target Proteome Profiler. We also transferred serum from sham/SNI mice to naïve mice to determine the potential of systemic contribution to pain. While nerve injury did not affect immune cell composition in the blood, it triggered a long-lasting disturbance of molecular profile in the serum of sham/SNI mice, in a sex-dependent manner. Compared to sham surgery, nerve injury amplified regulation of inflammatory proteins in males, but slightly reduced it in females. These changes in the serum occurred in parallel with long-lasting mechanical and cold hypersensitivity in the nerve-injured mice. Both male and female SNI serum induced hypersensitivity when transferred to naïve mice, regardless of a sex-matched or sex-mismatched transfer. Our results highlight that a local nerve injury can have persistent systemic impact. Injury-associated systemic inflammation could contribute to neuropathic pain, but the underlying mechanisms may be sexually dimorphic.

尽管神经损伤相关的神经炎症有助于神经性疼痛，但这种损伤对全身稳态的长期影响及其在疼痛中的潜在作用仍然难以捉摸。在这项研究中，我们旨在了解神经损伤的雄性和雌性小鼠在其整个生命周期中伴随慢性疼痛而出现的系统性变化。我们监测了雄性和雌性小鼠的机械和冷敏感性，从3-4个月大开始，当它们接受了神经损伤（SNI），直到损伤后20个月。此外，我们收集血液样本，用流式细胞术跟踪免疫细胞的变化，并使用111靶点蛋白质组分析器评估炎症相关的血清蛋白质组。我们还将假手术/SNI小鼠的血清转移到naïve小鼠身上，以确定全身对疼痛的潜在贡献。虽然神经损伤不影响血液中的免疫细胞组成，但它会以性别依赖的方式引发sham/SNI小鼠血清中分子谱的长期紊乱。与假手术相比，神经损伤放大了雄性炎症蛋白的调节，但在雌性中略有降低。血清中的这些变化与神经损伤小鼠的长期机械和冷超敏反应同时发生。无论性别匹配还是性别不匹配，雄性和雌性SNI血清在转移到naïve小鼠时均引起超敏反应。我们的结果强调，局部神经损伤可以有持续的全身性影响。损伤相关的全身性炎症可能导致神经性疼痛，但潜在的机制可能是两性二态的。

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引用次数: 0

Nrxn3 reduces myofascial nociceptive pain Nrxn3减轻肌筋膜痛觉性疼痛

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 DOI: 10.1016/j.ynpai.2025.100197

Lauren Nguyen, Mikhail Umorin, Phillip R. Kramer

Neurexin 3 (Nrxn3) has a role in neuronal signaling. Previous reports indicated that reducing Nrxn3 expression in the central amygdala increased orofacial neuropathic pain. A common temporomandibular disorder is myofascial pain. Thus, we hypothesized that Nrxn3 would reduce myofascial hypersensitivity. To test this hypothesis Nrxn3 shRNA was infused into the central amygdala of male rats. Then a ligature of the tendon attachment of the anterior superficial portion of the masseter muscle was performed to induce inflammatory orofacial pain. Dark phase meal duration was measured continuously, and von Frey filament testing was completed every 7 days for 21 days to measure the nociceptive response. After testing tissues were collected and the amount of Nrxn3 was measured. Neuronal activity in the orofacial pain pathway was quantitated by c-Fos staining of the central amygdala, lateral parabrachial nucleus, trigeminal ganglia and trigeminal nucleus caudalis. Knockdown of Nrxn3 in the central amygdala significantly increased the pain response and increased the levels of c-Fos. This increased response was observed for greater than two weeks. The data suggests Nrxn3 expression within the central amygdala attenuates nociceptive orofacial pain by reducing neuronal activity.

Neurexin 3 （Nrxn3）在神经元信号传导中起作用。先前的报道表明，减少中央杏仁核中Nrxn3的表达会增加口面部神经性疼痛。常见的颞下颌疾病是肌筋膜疼痛。因此，我们假设Nrxn3可以减少肌筋膜过敏。为了验证这一假设，我们将Nrxn3 shRNA注入雄性大鼠的中央杏仁核。然后对咬肌前浅表部分的肌腱连接进行结扎，以诱导炎症性口面部疼痛。连续测量暗相进食时间，每隔7天进行von Frey细丝测试，连续21天测量伤害反应。试验结束后，收集组织，测定Nrxn3的含量。采用c-Fos染色法对中央杏仁核、外侧臂旁核、三叉神经节和三叉尾核进行定量分析。中枢杏仁核中Nrxn3的下调显著增加了疼痛反应，并增加了c-Fos水平。观察到这种增加的反应超过两周。数据表明，中央杏仁核内Nrxn3的表达通过减少神经元活动来减轻伤害性口面部疼痛。

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引用次数: 0

Brain aging among individuals with trigeminal neuralgia 三叉神经痛患者的脑老化

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-07-01 DOI: 10.1016/j.ynpai.2025.100201

Yenisel Cruz-Almeida , Pedro A. Valdes-Hernandez , Yun Liang , Mingzhou Ding , John K. Neubert

Trigeminal neuralgia (TN) is a complex orofacial neuropathic pain condition with limited understanding of underlying mechanisms and therapeutic options. Emerging evidence suggests the involvement of the brain in persons with TN including widespread brain changes when employing a widely used brain aging biomarker that estimates a predicted brain age difference or brain age gap. The aim of the present cross-sectional study was to assess the predicted brain age difference (brain-PAD) or brain age gap across two TN subtypes (classical TN, and secondary/idiopathic TN) in comparison with age-and sex-matched pain-free controls and its association with several clinical and psychological characteristics. Thirty-four individuals diagnosed with Classical TN, 17 diagnosed with secondary/idiopathic TN were age- and sex-matched to pain-free controls (n = 54). All participants underwent a T1 brain MRI and completed clinical and psychological measures. There were significant differences in brain-PAD among TN subtypes (ANCOVA p = 0.0078, effect size f² = 0.28²), with individuals diagnosed with Classical TN having a brain-PAD significantly greater than the controls by 3.87 years (p = 0.01, Bonferroni-corrected). There were no significant brain-PAD differences between secondary/idiopathic TN and pain-free controls. Brain-PAD had a significant positive association with both pain catastrophizing (p < 0.05) and pain-related anxiety (p < 0.05), but no significant association with disease duration (p < 0.05) or usual pain intensity (p < 0.05) in persons with classical TN. The results were similar using a second brain aging biomarker. We report here accelerated brain aging processes in individuals with classical TN, but not in persons diagnosed with secondary/idiopathic TN. Our study replicates previous findings and adds to the literature that accelerated brain aging may not occur across all TN subtypes. Given the increased use of MRI for TN diagnostics, combined with our own recent work deriving brain aging biomarkers from clinical-grade scans, future studies within clinical settings are feasible and may help understand this debilitating condition.

三叉神经痛（TN）是一种复杂的口面部神经性疼痛，对其潜在机制和治疗方案的了解有限。新出现的证据表明，当使用广泛使用的脑衰老生物标志物来估计预测的脑年龄差异或脑年龄差距时，TN患者的大脑参与其中，包括广泛的大脑变化。本横断面研究的目的是评估两种TN亚型（经典TN和继发性/特发性TN）与年龄和性别匹配的无痛对照相比的预测脑年龄差异（脑- pad）或脑年龄差距及其与若干临床和心理特征的关联。34例诊断为经典TN， 17例诊断为继发性/特发性TN，年龄和性别与无痛对照组匹配（n = 54）。所有参与者都进行了T1脑MRI检查，并完成了临床和心理测量。脑- pad在TN亚型间存在显著差异（ANCOVA p = 0.0078，效应量f2 = 0.282），诊断为经典TN的个体脑- pad显著高于对照组3.87年（p = 0.01， bonferroni校正）。继发性/特发性TN与无痛对照组之间脑- pad无显著差异。在经典TN患者中，脑- pad与疼痛灾难化（p < 0.05）和疼痛相关焦虑（p < 0.05）均有显著正相关，但与疾病持续时间（p < 0.05）或通常疼痛强度（p < 0.05）无显著关联。使用第二种脑老化生物标志物，结果相似。我们在此报告了经典TN个体的加速脑老化过程，而不是诊断为继发性/特发性TN的人。我们的研究重复了以前的发现，并补充了文献，即加速脑老化可能不会发生在所有TN亚型中。鉴于MRI在TN诊断中的使用越来越多，结合我们自己最近从临床级扫描中获得脑老化生物标志物的工作，未来在临床环境中的研究是可行的，可能有助于了解这种使人衰弱的疾病。

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