Oxytocin: a pain disease-modifying agent in the nervous system after injury

催产素：神经系统受伤后的疼痛缓解剂

• 批准号: 10332259
• 负责人: James Eisenach
• 金额: $ 199.8万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10332259
• 关键词: Acute; Acute Pain; Address; Affective; Analgesics; Animals; Anti-Anxiety Agents; Anxiety; Area; Behavior; Behavioral; Blood; Brain; Cesarean section; Chronic; Clinical; Clinical Research; Cognitive; Computers; Data; Development; Disease; Dose; Drug Exposure; Drug Kinetics; Economics; Feasibility Studies; Female; Fiber; Formulation; Fright; Functional disorder; Goals; Human; Hypersensitivity; Infusion procedures; Injury; Intramuscular; Knowledge; Literature; Mechanoreceptors; Methods; Modeling; Nature; Nerve Block; Nerve Fibers; Nervous system structure; Neuraxis; Neuropathy; Nociception; Operative Surgical Procedures; Oxytocin; Pain; Pain Research; Patients; Pelvis; Penetration; Peripheral; Peripheral Nerves; Persons; Physical therapy; Physiological; Physiology; Process; Psychophysics; Rattus; Recovery; Reflex action; Reporting; Research; Resolution; Rodent; Role; Sensory; Site; Sleep; Social Behavior; Source; Speed; Sweden; Therapeutic; Time; Translations; Trust; Universities; Woman; addiction; behavior measurement; brain tissue; central sensitization; chronic pain; clinical practice; desensitization; disability; electrical property; human male; improved; in vivo; knee replacement arthroplasty; multimodality; neurophysiology; neuroprotection; pain behavior; pain chronification; pain reduction; pharmacodynamic model; pharmacokinetics and pharmacodynamics; postoperative recovery; pre-clinical; prevent; response; sensory stimulus; sex; social; tool; translational approach; translational study; transmission process; vibration perception

This P01 will address fundamental gaps in knowledge that currently impede translation of findings in the preclinical literature to improved clinical practice regarding the utility of oxytocin as a pain therapeutic and potential disease-modifying agent to prevent the transition from acute to chronic pain. Oxytocin itself is the only clinically available tool for translational studies in many areas – neuroprotection, anxiety, sleep, social behaviors, addiction, and pain. Most rodent and human studies of oxytocin lack strong scientific rigor, with only half of the clinical studies examining pain demonstrating efficacy, and we have minimal ability to understand oxytocin effects within and across species. Since chronic pain is usually reduced acutely by peripheral nerve block, peripheral input is necessary, but most research assumes that input is normal and pain reflects ongoing central sensitization. We and others challenge these ideas, showing that LTMRs are desensitized after injury whereas fast high threshold mechanoreceptors (A-HTMRs) are sensitized and behavioral recovery coincides with return to normal function of both afferent subtypes. Importantly, oxytocin acutely moves LTMR and A-HTMR dysfunction after injury towards normal. Pain resolves quicker in women after cesarean delivery than other pelvic surgeries, and hypersensitivity resolves quicker in rodents when neuropathic injury is performed after delivery, an effect blocked by inhibition of oxytocin action. These data suggest that oxytocin may alter the process of chronic pain development after injury or surgery, and has the potential to be not just an acute analgesic, but a disease-modifying therapeutic. Oxytocin has prosocial, anxiolytic, and trust enhancing effects according to small studies in rodents and humans, but the circuitry and role of these central actions on speeding recovery from pain and disability after injury are unexplored. This P01 will address these gaps and advance the field of pain research through the coordinated interactions between the preclinical and clinical projects across 3 specific areas. The first is extrapolation of the pharmacokinetics of oxytocin across species, such that drug exposure in relevant compartments with time are being studied in a coordinated manner that permits interpretation of physiological or behavioral effects between rats and humans Second is the study of primary sensory afferent physiology across species that determines how oxytocin alters specific nerve fiber types and the key electrical properties related to pain transmission, including multiple modes of nociceptive stimulation and their interaction. Third, we study pain behaviors beyond reflexive responses or verbal report in animals and humans, respectively, which may offer greater translational value. Collectively, the coordinated and synergistic nature of these studies will hopefully provide clarity on the potential of oxytocin to mitigate chronic pain development after injury, and the context within such effects occur.

本 P01 将解决目前阻碍研究结果转化的基本知识差距 临床前文献改善了有关催产素作为疼痛治疗剂的临床实践 潜在的疾病缓解剂，可防止急性疼痛转变为慢性疼痛。催产素本身是唯一 用于许多领域转化研究的临床可用工具——神经保护、焦虑、睡眠、社交 行为、成瘾和疼痛。大多数关于催产素的啮齿动物和人类研究缺乏严格的科学严谨性， 只有一半检查疼痛的临床研究显示出疗效，而我们的能力微乎其微 了解催产素在物种内部和物种之间的作用。由于慢性疼痛通常可以通过以下方式急剧减轻： 周围神经阻滞，外周输入是必要的，但大多数研究假设输入正常且疼痛 反映了持续的中央敏感化。我们和其他人对这些想法提出质疑，表明 LTMR 是 损伤后脱敏，而快速高阈值机械感受器 (A-HTMR) 则变得敏感并且 行为恢复与两种传入亚型恢复正常功能同时发生。重要的是，催产素 使受伤后的 LTMR 和 A-HTMR 功能障碍迅速恢复正常。女性的疼痛缓解得更快 与其他盆腔手术相比，剖腹产后，啮齿类动物的过敏反应更快地消失 神经性损伤是在分娩后发生的，这种作用可以通过抑制催产素的作用来阻断。这些数据 表明催产素可能会改变受伤或手术后慢性疼痛的发展过程，并且具有 它不仅有可能成为一种急性镇痛药，而且有可能成为一种缓解疾病的疗法。催产素具有亲社会性， 根据对啮齿动物和人类的小型研究，其具有抗焦虑和增强信任的作用，但电路和 这些核心行动在加速受伤后疼痛和残疾恢复方面的作用尚未被探索。这个P01 将解决这些差距并通过之间的协调互动推进疼痛研究领域 跨越 3 个特定领域的临床前和临床项目。第一个是药代动力学的外推 催产素跨物种，因此正在研究相关隔室中药物随时间的暴露 协调的方式，允许解释大鼠和人类之间的生理或行为影响 其次是对跨物种初级感觉传入生理学的研究，该生理学决定了催产素如何改变 特定的神经纤维类型和与疼痛传递相关的关键电特性，包括多个 伤害性刺激的模式及其相互作用。第三，我们研究反射之外的疼痛行为 分别在动物和人类中做出反应或口头报告，这可能提供更大的翻译价值。 总的来说，这些研究的协调和协同性质将有望澄清 催产素减轻受伤后慢性疼痛发展的潜力，以及这种影响的背景 发生。