Department of Anesthesiology, University of North Carolina, Chapel Hill, North Carolina; Institute for Trauma Recovery, University of North Carolina, Chapel Hill, North Carolina.
Department of Anesthesiology, University of North Carolina, Chapel Hill, North Carolina; Institute for Trauma Recovery, University of North Carolina, Chapel Hill, North Carolina; Department of Emergency Medicine, University of North Carolina, Chapel Hill, North Carolina.
J Pain. 2022 Jul;23(7):1256-1267. doi: 10.1016/j.jpain.2022.02.007. Epub 2022 Mar 14.
Chronic pain development is a frequent outcome of severe stressor exposure, with or without tissue injury. Enduring stress-induced hyperalgesia (ESIH) is believed to play a central role, but the precise mechanisms mediating the development of chronic post-traumatic pain, and the time-dependency of these mechanisms, remain poorly understood. Clinical and preclinical data suggest that the inhibition of FK506-binding protein 51 (FKBP51), a key stress system regulator, might prevent ESIH. We evaluated whether peritraumatic inhibition of FKBP51 in an animal model of traumatic stress exposure, the single prolonged stress (SPS) model, reversed ESIH evaluated via daily mechanical von Frey testing. FKBP51 inhibition was achieved using SAFit2, a potent and specific small molecule inhibitor of FKBP51, administered to male and female Sprague-Dawley rats via intraperitoneal injection. To assess timing effects, FKBP51 was administered at different times relative to stress (SPS) exposure. SAFit2 administration immediately after SPS produced a complete reversal in ESIH lasting >7 days. In contrast, SAFit2 administration 72 hours following SPS produced only temporary hyperalgesia reversal, and administration 120h following SPS had no effect. Similarly, animals undergoing SPS together with tissue injury (plantar incision) receiving SAFit2 immediately post-surgery developed acute hyperalgesia but recovered by 4 days and did not develop ESIH. These data suggest that: 1) FKBP51 plays an important, time-dependent role in ESIH pathogenesis, 2) time windows of opportunity may exist to prevent ESIH via FKBP51 inhibition after traumatic stress, with or without tissue injury, and 3) the use of inhibitors of specific pathways may provide new insights into chronic post-traumatic pain development. PERSPECTIVE: The current work adds to a growing body of literature indicating that FKBP51 inhibition is a highly promising potential treatment strategy for reducing hyperalgesia. In the case of post-traumatic chronic pain, we show that such a treatment strategy would be particularly impactful if administered early after traumatic stress exposure.
慢性疼痛的发展是严重应激源暴露的常见结果，无论是否有组织损伤。人们认为持久的应激诱导性痛觉过敏（ESIH）起着核心作用，但介导慢性创伤后疼痛发展的精确机制以及这些机制的时间依赖性仍知之甚少。临床和临床前数据表明，抑制 FK506 结合蛋白 51（FKBP51），一种关键的应激系统调节剂，可能预防 ESIH。我们评估了在创伤应激暴露的动物模型（即单一延长应激（SPS）模型）中，FKBP51 在创伤前抑制是否可以逆转通过每日机械 von Frey 测试评估的 ESIH。通过腹腔内注射，使用强效且特异的 FKBP51 小分子抑制剂 SAFit2 来实现 FKBP51 的抑制。为了评估时间效应，FKBP51 是在相对于应激（SPS）暴露的不同时间给予雄性和雌性 Sprague-Dawley 大鼠的。SAFit2 在 SPS 后立即给药会产生持续超过 7 天的 ESIH 完全逆转。相比之下，SAFit2 在 SPS 后 72 小时给药只会产生暂时的痛觉过敏逆转，而在 SPS 后 120 小时给药则没有效果。同样，接受 SPS 并同时接受足底切口组织损伤的动物在手术后立即接受 SAFit2 治疗会产生急性痛觉过敏，但在 4 天内恢复，并且不会发展为 ESIH。这些数据表明：1）FKBP51 在 ESIH 发病机制中起着重要的、时间依赖性的作用，2）在创伤后应激后，无论是否有组织损伤，通过 FKBP51 抑制可能存在预防 ESIH 的机会窗口，3）使用特定途径的抑制剂可能为慢性创伤后疼痛的发展提供新的见解。观点：目前的工作增加了越来越多的文献表明，FKBP51 抑制是减少痛觉过敏的一种很有前途的潜在治疗策略。在后创伤性慢性疼痛的情况下，如果在创伤后应激后早期给予这种治疗策略，其效果可能特别显著。
