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

点击翻译按钮获取中文摘要

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.