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。现代治疗学 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 血清转移关节炎模型在小鼠关节产生持久但可逆的炎症 伴随着早期起病的超敏，在炎症消退后仍持续很长时间 指数。在模型的早期阶段，疼痛行为对非类固醇抗炎药有反应 (非甾体类抗炎药)和阻断脊髓致敏的药物(例如加巴喷丁)，而在炎症后晚期， 疼痛只对后一种药物有反应。这种行为特征伴随着背侧持续的激活。 角质小胶质细胞与神经传入损伤标志物激活转录因子3的表达 背根神经节(DRG)，在男性和女性中，表明两性从炎症性到 一种神经病态的表型。出乎意料的是，尽管有神经损伤的证据，但雌性没有表现出 类似的晚期疼痛状态。药理学研究和对突变小鼠的研究揭示了几个 问题。1)向神经病变表型的转变受脊髓Toll样受体4的调节 (TLR4)信号和T和/或B细胞，在相关基因敲除菌株中，疼痛的解决证明。在女性中 由于缺乏T和B细胞，痛觉超敏的消退基本不受影响。2)我们的工作表明，TLR4信号， 主要通过MyD88与男性促炎症(TNF)信号的同时激活有关 导致持续的炎症后神经病理性疼痛状态。3)TLR4也通过TRIF和干扰素传递信号 (干扰素)，我们发现它可以减弱TLR4-MyD88信号的痛觉效应。我们推测这是 成分解释了女性缺乏晚期痛觉异常的原因。4)根据目前的证据，我们认为 在初级传入神经中有持续的但可逆的炎症、发芽和神经瘤样结构 节后交感神经传出位于关节和背根神经节的外周末端。 K/BxN男性和女性。这种萌发是由TLR4驱动的，TLR4激活炎症细胞和DRG 卫星细胞释放生长因子，这些生长因子触发/维持发芽并促进神经纤维迁移到 背根节和脊髓。5)脊髓TLR4参与痛觉加工可能是男性特有的， 女性优先使用适应性免疫细胞(T/B淋巴细胞)。然而，我们认为，无论是男女 使用适应性免疫细胞和TLR4信号，但程度不同。性别对这一转变的影响以及 到目前为止，还没有对潜在的萌发进行描述。具体地说，这些研究使用了K/BxN模型 男性和女性将表征疼痛、发芽(传入和交感)随时间的变化 DRG和踝关节)、炎症细胞向DRG和脊髓的迁移、神经胶质细胞的激活以及 性别、TLR4信号和T/B细胞在这些终点处。