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, GRĪ², 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.