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

本P01将解决目前阻碍将研究结果转化为 关于催产素作为疼痛治疗剂的效用的临床前文献， 潜在的疾病调节剂，以防止从急性疼痛转变为慢性疼痛。催产素本身是唯一 临床上可用于许多领域转化研究的工具-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强有力的科学严谨性， 只有一半的临床研究检查疼痛证明疗效，我们有最小的能力， 了解催产素在物种内部和物种之间的作用。由于慢性疼痛通常通过以下方式急性减轻 外周神经阻滞，外周输入是必要的，但大多数研究假设输入是正常的， 反映了正在进行的中央宣传。我们和其他人挑战这些想法，表明LTMR是 损伤后脱敏，而快高阈值机械感受器（A-HTMR）被敏化， 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功能障碍朝向正常。女性疼痛缓解更快 剖腹产后比其他盆腔手术，和超敏反应解决更快的啮齿动物时， 神经病性损伤在分娩后发生，这种作用被催产素作用的抑制所阻断。这些数据 表明催产素可能改变损伤或手术后慢性疼痛发展的过程， 不仅是一种急性镇痛药，而且是一种改善疾病的治疗药物。催产素具有亲社会性， 根据对啮齿动物和人类的小型研究， 这些中枢作用对加速从受伤后的疼痛和残疾中恢复的作用还没有被探索。P01 将解决这些差距，并通过协调之间的相互作用，推进疼痛研究领域 临床前和临床项目跨越3个特定领域。第一个是外推的药代动力学 催产素跨物种，这样，药物暴露在相关隔室与时间正在研究中， 协调的方式，允许解释大鼠和人类之间的生理或行为效应 第二个是跨物种的初级感觉传入生理学的研究，它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，包括多种 伤害性刺激的模式及其相互作用。第三，我们研究的疼痛行为超出了反射性， 反应或口头报告，分别在动物和人类，这可能会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 催产素减轻损伤后慢性疼痛发展的潜力，以及这种作用的背景 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.