Background & Aims

Stressful life events are known to exacerbate pain states but the underlying mechanisms linking pain with stress remain inadequately understood. A common regulator of stress and pain is the FK 506 binding protein 51 (FKBP51). FKBP51 modulates glucocorticoid receptor (GR) sensitivity and is therefore important for the regulation of the stress response. Furthermore, our lab has shown that FKBP51 is expressed in rodent central pain circuits and plays a key role in the development and maintenance of persistent pain states (Maiarù et al, 2016; Maiarù et al, 2018).
Here, we explored the possibility that FKBP51 may have a role in the increased vulnerability to persistent pain, specifically following exposure to stress in adulthood.

Methods

We used both adult male and female C57BL6 mice for this study. For stress exposure, mice were restrained in a falcon tube for 1 hour a day for three consecutive days. Inflammation was induced by intra-plantar injection of Complete Freund’s Adjuvant (CFA). Mechanical thresholds were assessed using Von Frey filaments applied to the hind-paw. Blood, brains and spinal cords of experimental mice were collected to investigate molecular mechanisms using ELISA, RT-qPCR, immunohistochemistry (IHC) and DNA methylation (DNAm) arrays.

Results

RS alone induced mechanical hypersensitivity in the hind-limb, resolving approximately one week after the end of the RS paradigm. There was an incremental increase in corticosterone over the course of the paradigm as well as an upregulation of spinal FKBP5, indicative of HPA axis activation. RS increased the magnitude and duration of hyperalgesia following subsequent hind-paw inflammation. This was accompanied by RS-induced changes in central pain circuits that led to increased expression of the immediate early gene, cFos, 2h after CFA injection and spinal upregulation of Fkbp5 48h after CFA. This increase in Fkbp5 expression was accompanied by an RS-induced decrease in DNAm in the Fkbp5 sequence. Moreover, pharmacological inhibition of FKBP51 during RS prevented the stress exacerbation of CFA-induced mechanical hypersensitivity.

Conclusions

These results show for the first time that RS primes for hyper-responsiveness to CFA-induced inflammation via FKBP51-dependent mechanisms. Furthermore, these effects are likely mediated by changes in DNA methylation along the gene. In conclusion, this study demonstrates that FKBP51 and its DNA methylation landscape may be crucial drivers of persistent pain vulnerability.

References

Maiarù, M., et al. (2016). The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling. Sci Trans Med, 8(325), 325ra19.
Maiarù, M., Morgan, O. B., et al. (2018). The stress regulator FKBP51: a novel and promising druggable target for the treatment of persistent pain states across sexes. Pain, 159(7), 1224–1234.

Presenting Author

Oakley B Morgan

Poster Authors

Oakley Morgan

PhD

McGill

Lead Author

E-mail

Samuel Singleton

PhD

University of Dundee

Lead Author

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Roxana Florea

University College London

Lead Author

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Sara Hestehave

University of Copenhagen, Department of Experimental Medicine

Lead Author

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Sandrine M Geranton PhD

University College London

Lead Author

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Topics

  • Models: Transition to Chronic Pain