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The Stress Regulator Fkbp51: A Novel and Promising Druggable Target for the Treatment of Persistent Pain States Across Sexes

Maiarù, M; Morgan, OB; Mao, T; Breitsamer, M; Bamber, H; Pöhlmann, M; Schmidt, MV; ... Géranton, SM; + view all (2018) The Stress Regulator Fkbp51: A Novel and Promising Druggable Target for the Treatment of Persistent Pain States Across Sexes. Pain , 159 (7) pp. 1224-1234. 10.1097/j.pain.0000000000001204. Green open access

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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 three 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 up-regulation of interleukin-6 in the spinal cord. Crucially, we were able to pharmacologically reduce the severity of the mechanical hypersensitivity seen in these three 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.

Type: Article
Title: The Stress Regulator Fkbp51: A Novel and Promising Druggable Target for the Treatment of Persistent Pain States Across Sexes
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1097/j.pain.0000000000001204
Publisher version: http://dx.doi.org/10.1097/j.pain.0000000000001204
Language: English
Additional information: Copyright © 2018 International Association for the Study of Pain. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: FKPB51; Dorsal horn; Glucocorticoid receptor; Glucocorticoid signalling; Persistent pain; Stress; Interleukin-6; Corticosterone; Pharmacological inhibition; Paclitaxel; Vesicular phospholipid gel
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10045697
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