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.

该P01将解决知识的基本差距 临床前文献改善了氧气作为疼痛治疗和 潜在的调整剂，以防止从急性到慢性疼痛的过渡。催产素本身是唯一的 在许多领域的临床上可转化研究工具 - 神经保护，焦虑，睡眠，社交 行为，成瘾和痛苦。大多数对氧加毒素的啮齿动物和人类研究都缺乏强大的科学严谨性，因为 只有一半 了解物种内部和跨物种内部的氧气作用。由于慢性疼痛通常被急性减轻 周围神经阻滞，外周输入是必要的，但是大多数研究都认为输入是正常的，疼痛 反映了正在进行的中央灵敏度。我们和其他人挑战了这些想法，表明LTMR是 受伤后脱敏，而快速的高阈值机制感受器（A-HTMR）是敏感的，并且 行为恢复与两个传入亚型的正常功能相吻合。重要的是，催产素 急性移动LTMR和A-HTMR功能障碍在正常情况下受伤。女性更快地解决疼痛 剖宫产后，比其他骨盆手术后，超敏反应在啮齿动物中更快地解决 分娩后进行神经性损伤，这种效应被抑制氧加毒素作用阻塞。这些数据 表明催产毒素可能会改变受伤或手术后慢性疼痛的过程，并具有 不仅是一种急性镇痛药，而且有可能是改良疾病的疗法。催产素有亲社会的， 根据啮齿动物和人类的小型研究，抗焦虑性和信任增强效果，但电路和电路 这些中心作用在伤害后加速疼痛和残疾康复方面的作用是出乎意料的。这个P01 将解决这些差距，并通过之间的协调相互作用来促进疼痛研究领域 跨三个特定领域的临床前和临床项目。首先是外推药物的药代动力学 跨物种的催产素，使相关隔室中的药物暴露在时间中 协调的方式允许对大鼠与人之间的身体或行为影响解释 第二是对跨物种的主要感觉传入生理学的研究，以决定催产素如何改变 特定的神经纤维类型和与疼痛传播相关的关键电特性，包括多个 伤害性刺激及其相互作用的模式。第三，我们研究反思性的疼痛行为 动物和人类中的反应或口头报告可能会提供更大的翻译价值。 总的来说，这些研究的协调性和协同性质将有望为 氧气的潜力减轻受伤后慢性疼痛的发展以及这种影响的背景 发生。