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

本P01将解决目前阻碍翻译#年调查结果的基本知识差距 关于催产素作为一种止痛和止痛药物的有效性的临床前文献 潜在的疾病改良剂，以防止从急性到慢性疼痛的过渡。催产素本身是唯一 临床上可用于多个领域的翻译研究工具-神经保护、焦虑、睡眠、社交 行为、上瘾和疼痛。大多数啮齿动物和人类对催产素的研究缺乏很强的科学严谨性， 检查疼痛的临床研究中只有一半证明了有效性，而且我们几乎没有能力 了解催产素在物种内和物种间的影响。由于慢性疼痛通常通过以下方式显著减轻 周围神经阻滞，外周输入是必要的，但大多数研究假设输入是正常的和疼痛的 反映了正在进行的中枢敏感化。我们和其他人对这些想法提出了挑战，表明LTM是 损伤后脱敏，而快速高阈值机械感受器(A-HTMR)敏化并 行为恢复与两种传入亚型的正常功能恢复一致。重要的是，催产素 急性地使损伤后的LTMR和A-HTMR功能障碍恢复正常。女性的疼痛消退得更快 与其他骨盆手术相比，剖腹产后，啮齿类动物的过敏反应更快地缓解 神经病理损伤是在分娩后进行的，这种作用被催产素作用的抑制所阻断。这些数据 提示催产素可能改变损伤或手术后慢性疼痛的发展过程，并具有 可能不仅是一种急性止痛药，还可能是一种治疗疾病的药物。催产素有亲社会的作用， 根据对啮齿动物和人类的小型研究，抗焦虑和增强信任的效果，但电路和 这些中枢作用在加速受伤后疼痛和残疾的恢复方面的作用尚不清楚。本P01 将通过以下方面的协调互动来解决这些差距并推进疼痛研究领域 3个特定领域的临床前和临床项目。第一种是外推阿司匹林的药代动力学。 催产素跨物种，因此相关隔室中的药物暴露随时间的变化正在进行研究 协调的方式，允许解释大鼠和人类之间的生理或行为影响 第二是跨物种初级感觉传入生理学的研究，它决定了催产素是如何改变的。 特定的神经纤维类型和与疼痛传递相关的关键电学特性，包括 伤害性刺激的方式及其相互作用。第三，我们研究了超越反射的疼痛行为。 动物和人类的反应或口头报告，这可能提供更大的翻译价值。 总体而言，这些研究的协调和协同性质有望澄清 催产素减轻损伤后慢性疼痛发展的潜力及其影响的背景 发生。

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.