Sex, Stress and Immunity in the Acute to Chronic Pain Transition

急性疼痛向慢性疼痛转变中的性、压力和免疫力

• 批准号: 10063577
• 负责人: TONY L. YAKSH
• 金额: $ 33.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063577
• 关键词: Acute; Address; Ankle; Appearance; Arthralgia; Arthritis; Astrocytes; Attenuated; B-Cell Activation; B-Lymphocytes; Behavioral; Cells; Chemical Sympathectomy; Event; Female; Functional disorder; Glial Fibrillary Acidic Protein; Growth Factor; IFNAR1 gene; Immune; Immune signaling; Immunity; Inflammation; Inflammatory; Injury; Interferon Activation; Interferons; Joints; K/BxN model; Ketorolac; Knock-out; Lymphocyte; Mediating; Microglia; Minocycline; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Mus; Mutant Strains Mice; Nerve; Nerve Fibers; Nerve Growth Factors; Neuroma; Neurons; Neuropathy; Non-Steroidal Anti-Inflammatory Agents; Pain; Peripheral; Persistent pain; Pharmaceutical Preparations; Pharmacology Study; Phase; Phenotype; Play; Prothrombin; Quality of life; Rag1 Mouse; Research; Resolution; Role; SB 203580; Sensory; Serum; Signal Transduction; Spinal; Spinal Anesthesia; Spinal Cord; Spinal Ganglia; Stress; Structure; Sympathetic Nerve Block; T-Lymphocyte; TLR4 gene; TNF gene; Therapeutic; Time; Transcription Factor 3; Transcriptional Activation; Tyrosine 3-Monooxygenase; Work; allodynia; ankle joint; base; cell motility; cell type; chronic pain; conditioned place preference; dorsal horn; early onset; fluorocitrate; gabapentin; glial activation; improved; indexing; inflammatory neuropathic pain; inflammatory pain; inhibitor/antagonist; joint inflammation; macrophage; male; migration; nerve injury; p38 Mitogen Activated Protein Kinase; pain behavior; pain chronification; pain processing; painful neuropathy; propentofylline; satellite cell; sex; therapy development

Arthralgia broadly impacts quality of life because of joint dysfunction and associated pain. Current therapeutics improve management of the arthritic joint but may not satisfactorily address the associated pain. The K/BxN serum transfer model of arthritis produces a long lasting, but reversible inflammation of the joint in mice accompanied by an early onset allodynia that surprisingly persists long after the resolution of inflammatory indices. In the early phase of the model, pain behavior responds to nonsteroidal anti-inflammatory drugs (NSAIDs) and agents that block spinal sensitization (e.g. Gabapentin), while in the post-inflammatory late phase, pain only responds to the latter agents. This behavioral profile is accompanied by a persistent activation of dorsal horn microglia and the appearance of activation transcription factor 3 (ATF3), a marker of afferent injury in the dorsal root ganglia (DRG), in males and females, suggesting a transition in both sexes from an inflammatory to a neuropathic phenotype. Unexpectedly, the female, despite evidence of nerve injury, does not display a comparable late phase pain state. Pharmacological studies and studies with mutant mice have revealed several issues. 1) Transition to a neuropathic phenotype is modulated by spinal Toll-like receptor 4 (TLR4) signaling and T and/or B cells evidenced by resolution of pain in relevant knock out strains. In females that lack T and B cells, resolution of allodynia is largely unaffected. 2) Our work indicates that TLR4 signaling, largely through MyD88 is associated with concurrent activation of proinflammatory (TNF) signaling in males leading to a persistent post inflammatory neuropathic pain state. 3) TLR4 also signals though TRIF and interferon (IFN), which we found to attenuate the algesic effects of TLR4-MyD88 signaling. We speculate that this component accounts for the lack of a late phase allodynia in the female. 4) Based on current evidence, we argue that with persistent, but reversible inflammation, sprouting and neuroma like structures in primary afferents and postganglionic sympathetic efferents occur at the peripheral terminals of the joint and the dorsal root ganglion of the K/BxN male and female. This sprouting is driven by TLR4, which activates inflammatory cells and DRG satellite cells to release growth factors, which trigger/sustain sprouting and promote migration of nerve fibers into the DRG and spinal cord. 5) Involvement of spinal TLR4 in pain processing was suggested to be male specific, and females to preferentially use adaptive immune cells (T/B lymphocytes). We believe however, that both sexes use adaptive immune cells and TLR4 signaling, but to varying degrees. The effects of sex on this transition and the underlying sprouting have not hitherto been characterized. Specifically, these studies using the K/BxN model in males and females will characterize time dependent changes in pain, sprouting (afferent and sympathetic in DRG and ankle), inflammatory cell migration into DRG and spinal cord, glial activation and the role played by sex, TLR4 signaling and T/B cells in these endpoints.

由于关节功能障碍和相关疼痛，关节痛广泛影响生活质量。当前治疗 改善关节炎关节的管理，但可能不能令人满意地解决相关的疼痛。K/BxN 关节炎的血清转移模型在小鼠中产生持久但可逆的关节炎症 伴随着在炎症消退后令人惊讶地持续很长时间的早发性异常性疼痛， 指数。在模型的早期阶段，疼痛行为对非甾体抗炎药有反应 （NSAID）和阻断脊髓敏化的药剂（例如加巴喷丁），而在炎症后晚期， 疼痛只对后者有反应。这种行为特征伴随着背侧神经元的持续激活。 角小胶质细胞和激活转录因子3（ATF 3）的出现，ATF 3是角小胶质细胞传入损伤的标志物， 背根神经节（DRG），在男性和女性，这表明在两种性别的过渡，从炎症到 神经病性表型。出乎意料的是，尽管有神经损伤的证据，这只雌性并没有表现出 类似的晚期疼痛状态。药理学研究和对突变小鼠的研究已经揭示了一些 问题. 1)脊髓Toll样受体4调节向神经病表型的转变 （TLR 4）信号传导和T和/或B细胞的作用，这通过相关敲除菌株中疼痛的消退来证明。雌性 缺乏T和B细胞，异常性疼痛的消退在很大程度上不受影响。2)我们的工作表明TLR 4信号， 主要通过MyD 88与男性中促炎性（TNF）信号传导的同时激活相关 导致持续的炎症后神经性疼痛状态。3)TLR 4也通过TRIF和干扰素发出信号 (IFN)我们发现，它减弱了TLR 4-MyD 88信号传导的痛觉效应。我们推测， 该成分解释了女性中缺乏晚期异常性疼痛。4)根据现有证据，我们认为 在初级传入神经中存在持续但可逆的炎症、发芽和神经瘤样结构， 节后交感神经传出发生在关节的外周末梢和背根神经节。 K/BxN男性和女性。这种发芽是由TLR 4驱动的，TLR 4激活炎症细胞和DRG 卫星细胞释放生长因子，触发/维持发芽，促进神经纤维迁移到 背根神经节和脊髓5)脊髓TLR 4参与疼痛处理被认为是男性特异性的， 女性优先使用适应性免疫细胞（T/B淋巴细胞）。然而，我们相信， 使用适应性免疫细胞和TLR 4信号，但程度不同。性别对这种转变的影响， 潜在的发芽迄今尚未被表征。具体而言，这些研究使用K/BxN模型 男性和女性的疼痛、发芽（传入和交感神经）的时间依赖性变化 DRG和踝关节），炎性细胞迁移到DRG和脊髓，胶质细胞活化以及 性别、TLR 4信号和T/B细胞。

项目成果

Complexity of systems and actions underlying neurogenic inflammation.

神经源性炎症的系统和作用的复杂性。

• DOI: 10.1007/s00281-018-0683-z
• 发表时间: 2018
• 期刊: Seminars in immunopathology
• 影响因子: 9
• 作者: Yaksh,TonyL;DiNardo,Anna
• 通讯作者: DiNardo,Anna

DRGquant: A new modular AI-based pipeline for 3D analysis of the DRG.

• DOI: 10.1016/j.jneumeth.2022.109497
• 发表时间: 2022-04-01
• 期刊: JOURNAL OF NEUROSCIENCE METHODS
• 影响因子: 3
• 作者: Hunt, Matthew A.;Lund, Harald;Delay, Lauriane;Dos Santos, Gilson Goncalves;Pham, Albert;Kurtovic, Zerina;Telang, Aditya;Lee, Adam;Parvathaneni, Akhil;Kussick, Emily;Corr, Maripat;Yaksh, Tony L.
• 通讯作者: Yaksh, Tony L.

Inhibition of Neuroinflammation by AIBP: Spinal Effects upon Facilitated Pain States.

• DOI: 10.1016/j.celrep.2018.04.110
• 发表时间: 2018-05-29
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Woller SA;Choi SH;An EJ;Low H;Schneider DA;Ramachandran R;Kim J;Bae YS;Sviridov D;Corr M;Yaksh TL;Miller YI
• 通讯作者: Miller YI

Inhibition of spinal 15-LOX-1 attenuates TLR4-dependent, nonsteroidal anti-inflammatory drug-unresponsive hyperalgesia in male rats.

• DOI: 10.1097/j.pain.0000000000001373
• 发表时间: 2018-12
• 期刊: Pain
• 影响因子: 7.4
• 作者: Gregus AM;Buczynski MW;Dumlao DS;Norris PC;Rai G;Simeonov A;Maloney DJ;Jadhav A;Xu Q;Wei SC;Fitzsimmons BL;Dennis EA;Yaksh TL
• 通讯作者: Yaksh TL

Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain.

脊柱小胶质细胞中胆固醇代谢的标准化减轻了神经性疼痛。

• DOI: 10.1084/jem.20202059
• 发表时间: 2021-07-05
• 期刊: The Journal of experimental medicine
• 作者: Navia-Pelaez JM;Choi SH;Dos Santos Aggum Capettini L;Xia Y;Gonen A;Agatisa-Boyle C;Delay L;Gonçalves Dos Santos G;Catroli GF;Kim J;Lu JW;Saylor B;Winkels H;Durant CP;Ghosheh Y;Beaton G;Ley K;Kufareva I;Corr M;Yaksh TL;Miller YI
• 通讯作者: Miller YI