FKBP51 antagonism to prevent chronic pain: optimizing efficacy & evaluating safety and mechanisms

项目摘要/摘要 每年有超过4000万美国人在创伤应激暴露(TSE)后寻求紧急护理。一个 这些人中有相当大一部分人面临慢性疼痛和共病阿片类药物的风险。 使用/误用。那些具有发展成慢性疼痛的高风险的人很容易被识别(例如，通过急性疼痛的严重程度)， 每年为预防慢性疼痛和相关阿片类药物创造数千万个机会 使用/误用。然而，没有任何干预措施可以防止高危人群出现慢性疼痛。事实上, 目前的药物要么对风险没有影响，要么实际上增加了风险。 TSE后疼痛的治疗目标历来侧重于与组织损伤相关的疼痛产生因素，但 越来越多的证据表明，参与应激反应的生理系统在 TSE后慢性疼痛的发展，开辟了一个令人兴奋的潜在治疗靶点的新景观。 在这种情况下，没有一个靶点比FK506结合蛋白51(FKBP51)更有希望。 已知细胞内蛋白影响糖皮质激素负反馈抑制。调查人员的数据 证明FKBP51抑制可逆转TSE后的痛觉过敏，并提示FKBP51抑制在TSE后 TSE可预防应激性痛觉过敏(ESIH)。调查人员的数据进一步证明， 抑制FKBP51对TSE后ESIH的影响具有时间、剂量和时间依赖性。现有文献 表明FKBP51水平升高不仅与TSE后的慢性疼痛有关，而且与其他 创伤后神经精神障碍往往伴有慢性疼痛和阿片类药物的使用/滥用，包括 创伤后应激、抑郁和焦虑。重要的是，调查小组的初步数据表明 抑制FKBP51不会对心脏产生不良影响，也不会对健康或行为产生其他不良影响。 在这些数据的基础上，调查小组将执行下一个关键步骤，以评估FKBP51作为 治疗靶点，包括(1)评估FKBP51抑制剂量、时机和持续时间的影响 TSE对ESIH的发展，(2)评估FKBP51预防作用的候选机制 抑制慢性疼痛的发展，以及(3)进行广泛的安全性和成瘾倾向测试。全 实验将在实验室、动物模型、疼痛测量、动物种类和动物之间进行 性别和年龄，由人类和动物ESIH、动物行为和成瘾方面的多学科专家团队提供 研究，FKBP51生物学，以及FKBP51抑制。这些实验的完成将大大推进 了解具有预防慢性疼痛和阿片类药物使用/滥用的令人兴奋的潜力的目标 在机动车碰撞等创伤应激暴露的早期寻求治疗的美国人， 每年都有性侵犯和身体侵犯。

PROJECT SUMMARY/ABSTRACT More than 40 million Americans seek emergency care after traumatic stress exposure (TSE) each year. A substantial proportion of these individuals are at risk for chronic pain development and comorbid opioid use/misuse. Those at high risk of developing chronic pain can easily be identified (e.g., by severity of acute pain), creating tens of millions of opportunities each year for the prevention of chronic pain and associated opioid use/misuse. However, no interventions exist that prevent chronic pain development in those at high risk. In fact, current medications either have no effect on risk or actually increase risk. Therapeutic targets for post-TSE pain have historically focused on tissue injury-related pain generators, but increasing evidence suggests that physiologic systems involved in the stress response play a critical role in chronic pain development after TSE, opening up an exciting new landscape of potential therapeutic targets. Within this landscape, no target appears more promising than FK506-binding protein 51 (FKBP51), an intracellular protein known to affect glucocorticoid negative feedback inhibition. The investigators’ data demonstrate that FKBP51 inhibition reverses hyperalgesia after TSE, and suggest that FKBP51 inhibition after TSE can prevent enduring stress-induced hyperalgesia (ESIH). The investigators’ data further demonstrate that the effects of FKBP51 inhibition on ESIH after TSE are time, dosing, and duration-dependent. Available literature indicate that increased FKBP51 levels are associated not only with chronic pain after TSE, but also with other post-traumatic neuropsychiatric disorders often comorbid with chronic pain and opioid use/abuse, including posttraumatic stress, depression, and anxiety. Importantly, preliminary data from the investigative team indicate that FKBP51 inhibition does not have adverse cardiac effects or other adverse health or behavioral effects. Building on these data, the investigative team will perform the next critical steps in evaluating FKBP51 as a therapeutic target, including (1) evaluating the influence of dose, timing, and duration of FKBP51 inhibition after TSE on ESIH development, (2) assessing candidate mechanisms mediating the preventive effect of FKBP51 inhibition on chronic pain development, and (3) performing extensive testing of safety and addiction liability. All experiments will be performed across laboratories, animal models, pain measures, animal species, and animal sex and age, by a multidisciplinary team of experts in human and animal ESIH, animal behavior and addiction studies, FKBP51 biology, and FKBP51 inhibition. Completion of these experiments will substantively advance understanding of a target with exciting potential to prevent chronic pain and opioid use/misuse in millions of Americans who seek care in the early aftermath of traumatic stress exposures such as motor vehicle collision, sexual assault, and physical assault each year.