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

The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling
The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling
Polymorphisms in FKBP51 are associated with stress-related psychiatric disorders and influence the severity of pain symptoms experienced after trauma. We report that FKBP51 (FK506 binding protein 51) is crucial for the full development and maintenance of long-term pain states. Indeed, FKBP51 knockout mice, as well as mice in which silencing of FKBP51 is restricted to the spinal cord, showed reduced hypersensitivity in several persistent pain models in rodents. FKBP51 deletion did not compromise the detection of acute painful stimuli, a critical protective mechanism. Moreover, the intrathecal administration of the specific FKBP51 inhibitor SAFit2 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 knockout mice. This finding suggested that FKBP51 regulates chronic pain by modulation of glucocorticoid signaling. Thus, 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.
1946-6234
Maiarù, Maria
38e94888-e565-414b-8717-ad37b9ce1483
Tochiki, Keri K.
12411fc1-4b9f-48e3-a393-7460874acc2f
Cox, Marc B.
c89b0a8c-08cb-4e8c-a97c-e393a48c07dc
Annan, Leonette V.
28495224-686e-40ab-8c5d-f5bd7e13aded
Bell, Christopher G.
44982df7-0746-4cdb-bed1-0bdfe68f1a64
Feng, Xixi
de65e3ea-f7f2-48d4-9c63-8ad31a41219d
Hausch, Felix
77a1d9ec-c6f3-4d51-9bd1-cd206e49ef11
Géranton, Sandrine M.
33090c84-70f1-42f7-8a5e-ed29414c2644
Maiarù, Maria
38e94888-e565-414b-8717-ad37b9ce1483
Tochiki, Keri K.
12411fc1-4b9f-48e3-a393-7460874acc2f
Cox, Marc B.
c89b0a8c-08cb-4e8c-a97c-e393a48c07dc
Annan, Leonette V.
28495224-686e-40ab-8c5d-f5bd7e13aded
Bell, Christopher G.
44982df7-0746-4cdb-bed1-0bdfe68f1a64
Feng, Xixi
de65e3ea-f7f2-48d4-9c63-8ad31a41219d
Hausch, Felix
77a1d9ec-c6f3-4d51-9bd1-cd206e49ef11
Géranton, Sandrine M.
33090c84-70f1-42f7-8a5e-ed29414c2644

Maiarù, Maria, Tochiki, Keri K., Cox, Marc B., Annan, Leonette V., Bell, Christopher G., Feng, Xixi, Hausch, Felix and Géranton, Sandrine M. (2016) The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling. Science Translational Medicine, 8 (325), [325ra19]. (doi:10.1126/scitranslmed.aab3376). (PMID:26865567)

Record type: Article

Abstract

Polymorphisms in FKBP51 are associated with stress-related psychiatric disorders and influence the severity of pain symptoms experienced after trauma. We report that FKBP51 (FK506 binding protein 51) is crucial for the full development and maintenance of long-term pain states. Indeed, FKBP51 knockout mice, as well as mice in which silencing of FKBP51 is restricted to the spinal cord, showed reduced hypersensitivity in several persistent pain models in rodents. FKBP51 deletion did not compromise the detection of acute painful stimuli, a critical protective mechanism. Moreover, the intrathecal administration of the specific FKBP51 inhibitor SAFit2 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 knockout mice. This finding suggested that FKBP51 regulates chronic pain by modulation of glucocorticoid signaling. Thus, 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.

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maiaru_stm_16_FKBP51_pain-Final-Draft.pdf - Accepted Manuscript
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Accepted/In Press date: 17 January 2016
e-pub ahead of print date: 10 February 2016
Published date: 10 February 2016
Organisations: Faculty of Natural and Environmental Sciences, Human Development & Health, MRC Life-Course Epidemiology Unit

Identifiers

Local EPrints ID: 390760
URI: http://eprints.soton.ac.uk/id/eprint/390760
ISSN: 1946-6234
PURE UUID: 3cb55a8d-c35a-43a6-95bc-62bf7c1724e1
ORCID for Christopher G. Bell: ORCID iD orcid.org/0000-0003-4601-1242

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Date deposited: 08 Apr 2016 16:01
Last modified: 15 Feb 2021 17:31

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