Mechanisms of chronic pain maintained by ongoing nociceptor inputs in females

女性持续伤害感受器输入维持慢性疼痛的机制

• 批准号: 10442735
• 负责人: Jun-Ho La
• 金额: $ 34.56万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442735
• 关键词: Action Potentials; Acute; Address; Adult; Affect; Afferent Neurons; Amyloid beta-Protein; Animal Model; Area; Behavioral; Benchmarking; Capsaicin; Cells; Chronic; Clinical; Complex; Complex Regional Pain Syndromes; Data; Development; Electrophysiology (science); Estrogens; FRAP1 gene; Female; GPER gene; High Prevalence; Hypersensitivity; Immune; Inflammation; Injections; Injury; Knowledge; Literature; Local Anesthetics; Local anesthesia; Maintenance; Mechanics; Mediating; Modeling; Molecular; Molecular Target; Mus; Nerve; Nerve Block; Neurons; Nociceptors; Opioid Analgesics; Pain; Pain management; Pathologic; Pathway interactions; Peripheral; Peripheral Nerves; Play; Preparation; Proteins; Public Health; Reporting; Research; Resolution; Signal Transduction; Site; Skin; Somatostatin; Spinal; Testing; Translations; Woman; Work; afferent nerve; base; central sensitization; chronic pain; chronic pain management; chronic painful condition; combat; dorsal horn; inhibitory neuron; mTOR Signaling Pathway; male; man; nerve damage; non-opioid analgesic; novel; opioid epidemic; opioid misuse; pain chronification; pain model; prescription opioid misuse; receptor; response; sex; sexual dimorphism

ABSTRACT Chronic pain afflicts >10% of US adults, with women being disproportionately affected, and constitutes a serious public health threat associated with overuse/misuse of opioid pain medications. Thus, new pain therapies based on detailed understanding of chronic pain mechanisms are needed as alternatives to opioid analgesics. Central sensitization is an important underlying contributor to chronic pain states, but it remains poorly understood how central sensitization persists when the inciting injury has apparently resolved. This proposal addresses female- specific mechanisms that maintain persistent central sensitization using a novel animal model that transitions from acute to chronic pain. This new model is based on the widely-used intradermal capsaicin injection model that normally develops short-lasting (1-3 days) central sensitization, resulting in mechanical hypersensitivity in areas outside the capsaicin injection site. We found that subsequent innocuous stimulation (e.g., warmth) of the capsaicin-injected hindpaw extended the central sensitization to more than two weeks, thus modeling pathological pain states where acute injury-induced temporary pain transitions to chronic pain despite resolution of the original injury. Both male and female mice develop persistent central sensitization, but the underlying mechanism(s) is sexually dimorphic in that a local anesthesia of the original injury site inhibits the persistent central sensitization only in females. This finding is reminiscent of clinical reports on 5 cases (4 women, 1 man) of complex regional pain syndrome in which local anesthesia of previous injury sites abolished mechanical hypersensitivity remote from the sites. Based on this observation and the literature, we hypothesize that the maintenance of central sensitization in females depends on persistent, ongoing peripheral nerve activity at the original injury site. We will test this hypothesis using the new female chronic pain model with behavioral, immunohistochemical, and electrophysiological approaches and determine the peripheral afferent types persistently active at the original injury site (Aim 1); the underlying molecular mechanism(s) of this persistent afferent activity (Aim 2); and central components contributing to the central sensitization maintained by persistent, ongoing afferent nerve activity (Aim 3). The results of this project will provide new knowledge of previously unrecognized female-specific chronic pain mechanisms and reveal peripheral and central targets for potential non-opioid chronic pain therapies in women, contributing to development of strategies to combat the ‘opioid epidemic’ caused by overuse/misuse of opioid analgesics.

抽象的 慢性疼痛苦难>美国成年人中有10％，女性受到不成比例的影响，构成严重 与过度使用/失误有关的公共卫生威胁。那是基于新的疼痛疗法 需要详细了解慢性疼痛机制，作为阿片类镇痛药的替代方法。中央 敏化是导致慢性疼痛状态的重要基础贡献者，但仍然很糟糕地了解 当煽动伤害显然解决时，中央灵敏度仍然存在。该提议解决了女性 - 使用新型动物模型来维持持久中心灵敏度的特定机制 从急性到慢性疼痛。该新模型基于广泛的皮内辣椒素注射模型 这通常会发展出短效率（1-3天）的中心灵敏度，从而导致机械性超敏反应 辣椒素注射部位以外的区域。我们发现随后的无害刺激（例如温暖） 辣椒素注射后爪将中心灵敏度扩展到了两周以上，因此建模 病理疼痛状态，急性损伤引起的暂时疼痛过渡到慢性疼痛目的地分辨率 原始伤害。雄性和雌性小鼠均表现出持久的中心灵敏度，但基础 机制是性二态性的，因为原始损伤部位的局部麻醉抑制了持久性 仅在女性中中心灵敏度。这一发现让人想起5例（4例女性，1名男性）的临床报告 复杂的区域疼痛综合征，其中先前受伤部位的局部麻醉废除了机械 高敏性远离站点。基于这一观察和文献，我们假设 维持女性中心敏感性取决于持续的，持续的周围神经活动 原始伤害现场。我们将使用具有行为的新女性慢性疼痛模型来检验这一假设， 免疫组织化学和电生理方法并确定外周传入类型 在原始伤害部位持续活跃（AIM 1）；该持久性的基本分子机制 传入活动（AIM 2）；以及有助于中心敏化的中央组成部分 持续的，持续的传入神经活动（AIM 3）。该项目的结果将提供有关的新知识 以前未识别的女性特异性慢性疼痛机制，并揭示了外围和中心目标 女性潜在的非阿片类药物慢性疼痛疗法，有助于制定战略 由阿片类镇痛药过度使用/失误引起的“阿片类流行病”。