The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling

Abstract

Polymorphisms in FKBP51 are associated with stress-related psychiatric disorders and influence the severity of pain symptoms experienced after trauma. Here, we report that FKBP51 (FK506 binding protein 51) is crucial for the full development and maintenance of long-term pain states and that this is independent from its effect on mood. Indeed, FKBP51 knock out mice but also mice with silencing of FKBP51 restricted to the spinal cord showed reduced hypersensitivity in a number of persistent pain models. FKBP51 deletion did not compromise the detection of acute painful stimuli, a critical protective mechanism. Moreover, the specific FKBP51 inhibitor SAFit2 intrathecally administered reduced the severity of an established pain state, confirming the crucial role of spinal FKBP51 in nociceptive processing. Finally, glucocorticoid signaling, which is known to modulate persistent pain states in rodents, was impaired in FKBP51 knock out mice. This suggested that FKBP51 regulates chronic pain by modulation of glucocorticoid signaling. In conclusion, FKBP51 is a central mediator of chronic pain, likely in humans as well as rodents, and is a new pharmacologically tractable target for the treatment of long term pain states. *To whom correspondence should be addressed: ucgasmg@ucl.ac.uk. Author contributions: SMG and MM designed the experiments, analyzed the data and wrote the manuscript. MM conducted all the behavioral experiments. MM and SMG conducted the RTqPCR and the glucocorticoid experiments. SG, MM and KKT conducted the immunohistochemical experiments. SMG and LVA conducted the DNA methylation studies. CGB designed the primers for the DNA methylation study. MBC provided the FKBP5 KO mice. FX and FH provided SAFit2.

Checks and balances: The glucocorticoid receptor and NFĸB in good times and bad

“…It is already known that following cognitive behavioral stress management, upregulated genes exhibit an overrepresentation of GREs and an underrepresentation of κREs, suggesting that with stress management, patients experience a shift to increased GR-mediated signaling and possibly more adaptive function (Antoni, Lutgendorf et al 2012). Additional therapeutic avenues may be feasible through modulation of the molecular mechanisms that mediate these transcription factors such as interventions at the level of FKBP5 (Hinds, Stechschulte et al 2014, Gaali, Kirschner et al 2015, Hartmann, Wagner et al 2015, Maiaru, Tochiki et al 2016) which interacts with both GR and NFκB (Rein 2016). Furthermore, several anti-inflammatory and anti-cytokine agents have been considered for the treatment of mood disorders with moderate success.…”

Stress-related psychological symptoms contribute to axial pain persistence after motor vehicle collision: path analysis results from a prospective longitudinal study

“…Animal data indicate that persistently elevated levels of cortisol sensitize primary afferents,[20] and that elevated spinal FKBP5 levels contribute to hypersensitivity and intracellular changes/switches that cause the cellular effects of glucocorticoids to change from analgesic to hyperalgesic. [24] Such molecular switches that cause stress molecules (e.g., glucocorticoids) to change from analgesic to hyperalgesic are fundamental to the development of chronic post-traumatic pain. In such individuals, hyperarousal symptoms, a dominant PTSD symptom cluster [25,35] known to drive the further activation of stress systems including hypothalamic-pituitary-adrenal and catecholaminergic systems,[45] may promote the cellular changes that underline chronic pain.…”

Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds

“…Significantly, FKBP51 blockade did not prevent acute pain responses and may be an effective strategy for novel analgesics to treat longlasting pain. 133 …”