Neurobiology of Pain最新文献_第3页

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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引用次数: 0

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 : 2025-05-22 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

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 : 2025-05-16 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

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 : 2025-05-08 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

Humanized NaV1.8 rats overcome cross-species potency shifts in developing novel NaV1.8 inhibitors 人源化的NaV1.8大鼠在开发新型NaV1.8抑制剂时克服了跨物种的效力变化

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-03-06 DOI: 10.1016/j.ynpai.2025.100182

Dillon S. McDevitt , Joshua D. Vardigan , Xiaoping Zhou , Thomas W. Rosahl , Heather Zhou , Eric A. Price , Michelle K. Clements , Yuxing Li , Nissi Varghese , Alicja Krasowska-Zoladek , Shawn J. Stachel , Michael J. Breslin , Christopher S. Burgey , Richard L. Kraus , Parul S. Pall , Darrell A. Henze , Vincent P. Santarelli

Voltage-gated sodium channel isoform 1.8 (Na_V1.8) has emerged as a promising pharmaceutical target for the treatment of acute and chronic pain. However, highly selective and potent inhibitors for this channel have been difficult to develop and only recently have advanced to clinical testing. Our efforts to develop Na_V1.8 small molecule inhibitors yielded a series of molecules with favorable in vitro potency and selectivity against the human Na_V1.8 channel but exhibited dramatic rightward potency shifts against the rodent channel, severely limiting in vivo screening and candidate selection. In anticipation of supporting drug discovery efforts, a transgenic rat line expressing the human Na_V1.8 channel in lieu of the rodent channel was developed. Utilizing these humanized animals, the in vitro potency of our chemical matter in freshly isolated humanized rat DRG neurons was consistent with in vitro human potency values, enabling in vivo work to progress. We demonstrate capsaicin-induced nocifensive behaviors (CNB) as a moderate throughput in vivo screening assay, from which we demonstrate pharmacokinetic-pharmacodynamic (PK-PD) and in vitro-in vivo correlation (IVIVC) relationships. We identified MSD199 as a potent Na_V1.8 inhibitor with acute pain efficacy and assessed it in traditional inflammatory (Complete Freund’s Adjuvant) and neuropathic (spinal nerve ligation) behavioral chronic pain assays where it was shown to significantly reduce pain-related behaviors. Overall, we demonstrate the utility of humanized transgenic animals when cross-species potency shifts are observed within an otherwise promising chemical series.

电压门控钠通道异构体1.8 （NaV1.8）已成为治疗急慢性疼痛的一个有前途的药物靶点。然而，这一通道的高选择性和强效抑制剂一直难以开发，直到最近才进入临床试验阶段。我们努力开发的NaV1.8小分子抑制剂产生了一系列对人类NaV1.8通道具有良好的体外效力和选择性的分子，但对啮齿动物通道表现出明显的右移效力，严重限制了体内筛选和候选物的选择。为了支持药物发现工作，开发了一种表达人类NaV1.8通道的转基因大鼠系来代替啮齿动物通道。利用这些人源化动物，我们的化学物质在新分离的人源化大鼠DRG神经元中的体外效力值与体外人效力值一致，使体内工作得以进行。我们证明了辣椒素诱导的有害行为（CNB）是一种中等通量的体内筛选试验，从中我们证明了药代动力学-药效学（PK-PD）和体外-体内相关（IVIVC）关系。我们确定MSD199是一种有效的NaV1.8抑制剂，具有急性疼痛疗效，并在传统的炎症（完全弗氏佐剂）和神经性（脊神经结扎）行为慢性疼痛试验中对其进行了评估，结果显示，MSD199可显著减少疼痛相关行为。总的来说，我们证明了当在其他有前途的化学系列中观察到跨物种效力变化时，人源化转基因动物的效用。

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引用次数: 0

Cerebral peak alpha frequency: Associations with chronic pain onset and pain modulation 脑α峰频率：与慢性疼痛发作和疼痛调节的关系

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-02-28 DOI: 10.1016/j.ynpai.2025.100180

Felicitas A. Huber , Parker A. Kell , Joanna O. Shadlow , Jamie L. Rhudy

Chronic pain is highly prevalent in the U.S. and leads to myriad negative sequalae and suffering. One way to address chronic pain is to identify who is at risk and intervene prior to symptom onset. Research suggests resting peak alpha frequency (PAF), the speed of alpha oscillations at rest, is slower in healthy individuals with greater pain sensitivity and in chronic pain patients. Thus, slower PAF may denote chronic pain vulnerability. Other research has shown that individuals at higher risk of chronic pain exhibit disrupted pain modulation, i.e., less efficient pain inhibition and increased pain facilitation. Currently, the ability of PAF to predict chronic pain and its relation to pain modulation is under-researched. This investigation aimed to address this gap by characterizing associations between PAF, onset of chronic pain, and pain modulation. Using archival data from three independent studies, this investigation assessed whether slower PAF is associated with prospectively-determined chronic pain onset, decreased pain inhibition (i.e., impaired conditioned pain modulation, impaired erotica-induced pain inhibition), and increased pain facilitation (i.e., increased temporal summation of pain, augmented mutilation-induced pain facilitation). Results show that slower PAF was associated with greater facilitation of spinal (i.e., nociceptive flexion reflex) and supraspinal (i.e., N2 potential) nociception in response to unpleasant pictures (i.e., human injury images). This suggests that slower PAF is associated with threat-enhanced spinal and supraspinal nociception and may be relevant for chronic pain conditions with disrupted threat systems. Slower PAF was not associated with any other pain outcome, including prospectively determined chronic pain onset. However, chronic pain onset could only be assessed in one study with a mixed eyes open/eyes closed recording, limiting the significance of this finding.

慢性疼痛在美国非常普遍，并导致无数的负面后遗症和痛苦。解决慢性疼痛的一种方法是确定谁处于危险之中，并在症状发作之前进行干预。研究表明，在疼痛敏感性较高的健康个体和慢性疼痛患者中，静息α峰值频率（PAF），即静息时α振荡的速度较慢。因此，较慢的PAF可能表示慢性疼痛易感性。其他研究表明，慢性疼痛风险较高的个体表现出疼痛调节紊乱，即疼痛抑制效率较低，疼痛促进能力增强。目前，PAF预测慢性疼痛的能力及其与疼痛调节的关系研究尚不充分。本研究旨在通过表征PAF、慢性疼痛发作和疼痛调节之间的关系来解决这一差距。利用三个独立研究的档案数据，本研究评估了PAF减慢是否与预期确定的慢性疼痛发作、疼痛抑制减弱（即条件性疼痛调节受损、性诱发疼痛抑制受损）和疼痛促进增强（即疼痛时间累积增加、残肢诱发疼痛促进增强）相关。结果表明，较慢的PAF与脊柱（即伤害性屈曲反射）和棘上（即N2电位）对不愉快图像（即人体损伤图像）的伤害感觉的更大促进有关。这表明，较慢的PAF与威胁增强的脊髓和椎管上伤害感觉有关，可能与威胁系统中断的慢性疼痛有关。较慢的PAF与任何其他疼痛结果无关，包括前瞻性确定的慢性疼痛发作。然而，慢性疼痛的发作只能在一项研究中通过混合睁眼/闭眼记录进行评估，限制了这一发现的意义。

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引用次数: 0

Voluntary exercise prevents and eradicates anxiety-like behavior by influencing parvalbumin-positive neurons, perineuronal nets, and microglia activation in corticolimbic regions of neuropathic pain rats 自愿运动通过影响神经性疼痛大鼠皮质边缘区的小蛋白阳性神经元、神经周围网和小胶质细胞激活来预防和根除焦虑样行为

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-02-27 DOI: 10.1016/j.ynpai.2025.100181

Thu Nguyen Dang , Cuong Nguyen Van , Ryosuke Ochi , Hiroki Kuwamura , Tomoyuki Kurose , Yoki Nakamura , Kazue Hisaoka-Nakashima , Norimitsu Morioka , Hisao Nishijo , Naoto Fujita , Susumu Urakawa

Anxiety-like behavior often emerges in the later stages of neuropathic pain, exacerbating the pain condition and potentially involving parvalbumin-positive (PV⁺) neurons. This study aimed to investigate the effects of voluntary exercise on neuropathic pain-induced anxiety and its relationship with PV⁺ neurons, perineuronal nets (PNNs, labeled with Wisteria floribunda agglutinin [WFA]), and microglia in the corticolimbic regions. Male Wistar rats with partial sciatic nerve ligation (PSL) were given access to running wheels either from 3 days (early voluntary exercise [EEx]) or from 4 weeks (late voluntary exercise [LEx]) postoperatively. Nociceptive behaviors were assessed using the von Frey and acetone tests, while anxiety-like behaviors were assessed using the open field and elevated plus maze tests. Brain sections were histologically analyzed using immunohistochemistry and immunofluorescence 8 weeks post-surgery. Both early and late exercise partially restored the paw withdrawal thresholds and the arousal response. PSL-EEx rats did not exhibit anxiety-like behaviors. PSL-LEx rats transiently showed anxiety-like behaviors, but these were eradicated by exercise. PSL altered PV⁺ neurons and PNNs in specific corticolimbic subregions. Notably, voluntary exercise restored the densities of PV⁺-strong WFA⁺ neurons in the basolateral amygdala, PV⁺-WFA^-, and PV⁺-WFA⁺ neurons in the anterior cingulate cortex, and PV⁺-WFA⁺ neurons in the hippocampal cornu ammonis 1. These changes correlated with reduced anxiety-like behaviors. Exercise modulated PSL-induced microglial activation and interacted differently with these neurons. These findings suggest that voluntary exercise prevents and eliminates chronic pain-induced anxiety through neuronal mechanisms other than analgesic effects, potentially involving PV⁺ neurons, PNNs, and microglia in the corticolimbic subregions.

焦虑样行为通常出现在神经性疼痛的后期，加剧疼痛状况，并可能涉及小蛋白阳性（PV+）神经元。本研究旨在探讨自主运动对神经性疼痛性焦虑的影响及其与皮质边缘区PV+神经元、周围神经元网（PNNs，标记有紫藤凝集素[WFA]）和小胶质细胞的关系。部分坐骨神经结扎（PSL）的雄性Wistar大鼠术后3天（早期自愿运动[EEx]）或4周（晚期自愿运动[LEx]）给予滚轮活动。伤害性行为采用von Frey和丙酮测试进行评估，而焦虑样行为采用开阔场和升高加迷宫测试进行评估。术后8周采用免疫组织化学和免疫荧光对脑切片进行组织学分析。早、晚运动均能部分恢复足爪退缩阈值和唤醒反应。PSL-EEx大鼠没有表现出焦虑样行为。PSL-LEx大鼠短暂表现出焦虑样行为，但这些行为通过运动消除。PSL改变了特定皮质边缘亚区PV+神经元和pnn。值得注意的是，自愿运动恢复了基底外侧杏仁核PV+-强WFA+神经元、前扣带皮层PV+-WFA-和PV+-WFA+神经元以及海马海马角的PV+-WFA+神经元的密度1。这些变化与减少焦虑行为有关。运动调节psl诱导的小胶质细胞激活，并与这些神经元发生不同的相互作用。这些发现表明，自愿运动通过非镇痛作用的神经元机制预防和消除慢性疼痛引起的焦虑，可能涉及皮质边缘亚区的PV+神经元、PNNs和小胶质细胞。

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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 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

Glial activation and nociceptive neuropeptide elevation associated with the development of chronic post-traumatic headache following repetitive blast exposure 神经胶质细胞激活和伤害神经肽升高与反复爆炸暴露后慢性创伤后头痛的发展有关。

Q2 Medicine

Neurobiology of Pain

Pub Date : 2025-01-01 DOI: 10.1016/j.ynpai.2024.100178

Amirah Wright , Susan F. Murphy , Pamela J. VandeVord

Chronic headaches and pain are prevalent in those who are exposure to blast events, yet there is a gap in fundamental data that identifies the pathological mechanism for the chronification of pain. Blast-related post-traumatic headaches (PTH) are understudied and chronic pain behaviors in preclinical models can be vital to help elucidate PTH mechanisms. The descending pain modulatory system controls pain perception and involves specific brain regions such as the cortex, thalamus, pons, and medulla. In this study, male rats were exposed to repeated blast events to induce traumatic brain injury (bTBI) and subsequently assessed for the development of PTH by testing for chronic pain behaviors and examining the neuropathology of the descending pain pathway. The results demonstrated that facial hypersensitivity developed as early as week two following bTBI and persisted throughout the study (12 weeks). Depressive-like behaviors were observed at 12 weeks following bTBI, and these behaviors were associated with neuropathologies such as microglia ramification and neuropeptide elevation (Calcitonin Gene-Related Peptide, CGRP; Substance P, SP). Overall, these findings support the hypothesis that bTBI causes the activation of microglia and elevation of neuropeptides, which contribute to the development of chronic PTH behaviors.

慢性头痛和疼痛在暴露于爆炸事件的人群中普遍存在，但在确定疼痛慢性化的病理机制的基础数据方面存在空白。爆炸相关的创伤后头痛（PTH）尚未得到充分研究，临床前模型中的慢性疼痛行为对阐明PTH机制至关重要。下行疼痛调节系统控制疼痛感知，涉及特定的大脑区域，如皮层、丘脑、脑桥和髓质。在这项研究中，雄性大鼠暴露于重复爆炸事件诱导创伤性脑损伤（bTBI），随后通过检测慢性疼痛行为和检查下行疼痛通路的神经病理学来评估PTH的发展。结果表明，面部过敏早在脑外伤后第2周就出现，并持续整个研究（12周）。在bTBI后12周观察到抑郁样行为，这些行为与神经病理相关，如小胶质细胞分支和神经肽升高(降钙素基因相关肽，CGRP；物质P， SP)。总的来说，这些发现支持了bTBI引起小胶质细胞激活和神经肽升高的假设，这有助于慢性PTH行为的发展。

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引用次数: 0