Stress, epigenetic remodeling and FKBP51: Pathways to chronic pain vulnerability

Abstract

Chronic pain and post-traumatic stress disorder (PTSD) show striking similarities in their prevalence following injury and trauma respectively, with growing evidence suggesting shared vulnerability mechanisms, particularly through stress-related epigenetic regulation. The gene FK506 binding protein 5, FKBP5, is a critical regulator of the stress response which plays a well-established role in PTSD susceptibility and has recently emerged as a potential driver of chronic pain vulnerability. In our pre-clinical study, sub-chronic stress promoted the persistence of subsequent inflammation-induced primary hyperalgesia and accelerated the development of inflammation-driven anxiety in male and female mice. Global deletion of Fkbp5 reduced stress-induced vulnerability to persistent pain, with a more pronounced protective effect in males than in females. To investigate the mechanisms underlying FKBP51-driven persistent pain vulnerability, we analysed male spinal cord tissue after stress exposure and found hypomethylation in the Fkbp5 promoter site for the canonical FKBP51 transcript and other stress-related genes. However, most epigenetic changes in key regulatory regions did not correlate with changes in gene expression, suggesting that stress exposure had remodelled the epigenome without altering gene activity. FKBP51 pharmacological inhibition in males during stress exposure shortened the duration of subsequent inflammatory pain and reversed several stress-induced DNA methylation changes in promoter regions of genes associated with stress and nociception, but not Fkbp5. These results indicate that sub-chronic stress increases the susceptibility to chronic pain in an FKBP51-driven mechanism and leads to the hypomethylation of Fkbp5. However, reversing Fkbp5 hypomethylation is not necessary to prevent chronic pain vulnerability, which is likely driven by complex epigenetic regulation.

Keywords: Chronic pain; DNA methylation; Epigenetics; Fkbp5; Stress; Vulnerability.