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

Maiarù, M; Tochiki, KK; Cox, MB; Annan, LV; Bell, CG; Feng, X; Geranton, SM; (2016) The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling. Science Translational Medicine , 8 (325) , Article 325ra19. 10.1126/scitranslmed.aab3376. Green open access

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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.

Type: Article
Title: The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/scitranslmed.aab3376
Publisher version: http://dx.doi.org/10.1126/scitranslmed.aab3376
Language: English
Additional information: This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine Vo. 8, iss. 325 on 11/02/16, DOI: 10.1126/scitranslmed.aab3376.
Keywords: FKBP51, chronic pain, glucocorticoid signaling, SAFit2, siRNA, DNA methylation
UCL classification: 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 Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
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/1474383
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