Abstract
It is well established that FKBP51 regulates the stress system by modulating the sensitivity of the glucocorticoid receptor to stress hormones. Recently, we have demonstrated that FKBP51 also drives long-term inflammatory pain states in male mice by modulating glucocorticoid signalling at spinal cord level. Here, we explored the potential of FKBP51 as a new pharmacological target for the treatment of persistent pain across the sexes. First, we demonstrated that FKBP51 regulates long-term pain states of different aetiologies independently of sex. Deletion of FKBP51 reduced the mechanical hypersensitivity seen in joint inflammatory and neuropathic pain states in female and male mice. Furthermore, FKBP51 deletion also reduced the hypersensitivity seen in a translational model of chemotherapy-induced pain. Interestingly, these 3 pain states were associated with changes in glucocorticoid signalling, as indicated by the increased expression, at spinal cord level, of the glucocorticoid receptor isoform associated with glucocorticoid resistance, GRβ, and increased levels of plasma corticosterone. These pain states were also accompanied by an upregulation of interleukin-6 in the spinal cord. Crucially, we were able to pharmacologically reduce the severity of the mechanical hypersensitivity seen in these 3 models of persistent pain with the unique FKBP51 ligand SAFit2. When SAFit2 was combined with a state-of-the-art vesicular phospholipid gel formulation for slow release, a single injection of SAFit2 offered pain relief for at least 7 days. We therefore propose the pharmacological blockade of FKBP51 as a new approach for the treatment of persistent pain across sexes, likely in humans as well as rodents.
Highlights
IntroductionThe FK506 binding protein 51 (FKBP51) is important for the regulation of the stress response, and polymorphisms of the FKBP51-encoding gene, FKBP5, have been associated with atypical stress axis reactivity, with high levels of FKBP51 protein
The FK506 binding protein 51 (FKBP51) is important for the regulation of the stress response, and polymorphisms of the FKBP51-encoding gene, FKBP5, have been associated with atypical stress axis reactivity, with high levels of FKBP51 proteinSponsorships or competing interests that may be relevant to content are disclosed at the end of this article. a Department of Cell and Developmental Biology, University College London, London, United Kingdom, b Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
We first examined whether FKBP51 regulated the development of the mechanical hypersensitivity seen with ankle joint inflammation in female mice through modulation of glucocorticoid signalling, as we have reported in male mice.[21]
Summary
The FK506 binding protein 51 (FKBP51) is important for the regulation of the stress response, and polymorphisms of the FKBP51-encoding gene, FKBP5, have been associated with atypical stress axis reactivity, with high levels of FKBP51 protein. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. A Department of Cell and Developmental Biology, University College London, London, United Kingdom, b Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany. Drs Tianqi Mao and Felix Hausch is with Institute of Organic Chemistry and Biochemistry, Technical University Darmstadt, Darmstadt, Germany, c Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-Universitat Munchen, Munich, Germany, d Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
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