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: 9431570
• 负责人: TONY L. YAKSH
• 金额: $ 9.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9431570
• 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; MAPK14 gene; 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; dorsal horn; early onset; fluorocitrate; gabapentin; glial activation; improved; indexing; inflammatory neuropathic pain; inflammatory pain; inhibitor/antagonist; macrophage; male; migration; nerve injury; pain behavior; painful neuropathy; preference; 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。目前的治疗方法 改善关节炎关节的治疗，但可能无法令人满意地解决相关疼痛。 K/BxN 关节炎的血清转移模型在小鼠体内产生持久但可逆的关节炎症 伴随着早发性异常性疼痛，令人惊讶的是，这种异常性疼痛在炎症消退后仍持续很长时间 指数。在模型的早期阶段，疼痛行为对非甾体抗炎药有反应 （非甾体抗炎药）和阻断脊髓敏化的药物（例如加巴喷丁），在炎症后后期， 疼痛仅对后者有反应。这种行为特征伴随着背侧的持续激活 角小胶质细胞和激活转录因子 3 (ATF3) 的出现，ATF3 是大脑中传入损伤的标志物 男性和女性的背根神经节（DRG），表明两性从炎症到炎症的转变 神经病表型。出乎意料的是，尽管有神经损伤的证据，雌性并没有表现出任何症状。 可比较的晚期疼痛状态。药理学研究和突变小鼠研究揭示了一些 问题。 1) 向神经病表型的转变由脊髓 Toll 样受体 4 调节 (TLR4) 信号传导和 T 和/或 B 细胞通过相关敲除菌株中疼痛的缓解得到证明。在女性中 如果缺乏 T 和 B 细胞，异常性疼痛的缓解基本上不受影响。 2) 我们的工作表明 TLR4 信号传导， 主要通过 MyD88 与男性促炎 (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) TLR4还通过TRIF和干扰素发出信号 (IFN)，我们发现它可以减弱 TLR4-MyD88 信号传导的镇痛作用。我们推测这 部分解释了女性缺乏晚期异常性疼痛。 4）根据现有证据，我们认为 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末梢和背根神经节 K/BxN 男性和女性。这种发芽是由 TLR4 驱动的，TLR4 会激活炎症细胞和 DRG 卫星细胞释放生长因子，触发/维持发芽并促进神经纤维迁移到 DRG 和脊髓。 5) 脊髓 TLR4 参与疼痛处理被认为是男性特有的， 女性优先使用适应性免疫细胞（T/B淋巴细胞）。但我们相信，无论男女 使用适应性免疫细胞和 TLR4 信号传导，但程度不同。性别对这种转变的影响 迄今为止，尚未对底层发芽进行表征。具体来说，这些研究使用 K/BxN 模型 男性和女性的特征是疼痛、萌芽（传入和交感神经）随时间的变化。 DRG 和踝关节），炎症细胞迁移到 DRG 和脊髓，胶质细胞活化及其所起的作用 这些终点中的性别、TLR4 信号传导和 T/B 细胞。