title: The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling.
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.
authors: Cell and Developmental Biology, University College London (UCL), London WC1E 6BT, UK.
authors: Maria
authors: M
authors: Maiarù
authors: Cell and Developmental Biology, University College London (UCL), London WC1E 6BT, UK.
authors: Keri K
authors: KK
authors: Tochiki
authors: Border Biomedical Research Center and Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79902, USA.
authors: Marc B
authors: MB
authors: Cox
authors: Cell and Developmental Biology, University College London (UCL), London WC1E 6BT, UK.
authors: Leonette V
authors: LV
authors: Annan
authors: Epigenomic Medicine, Centre for Biological Sciences, Institute of Developmental Sciences, S017 1BJ, and MRC (Medical Research Council) Lifecourse Epidemiology Unit, S016 6YD, University of Southampton, Southampton, UK.
authors: Christopher G
authors: CG
authors: Bell
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors: Xixi
authors: X
authors: Feng
authors: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors: Felix
authors: F
authors: Hausch
authors: Cell and Developmental Biology, University College London (UCL), London WC1E 6BT, UK. ucgasmg@ucl.ac.uk.
authors: Sandrine M
authors: SM
authors: Géranton
mesh_terms: D000818:Animals; D059350:Chronic Pain / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D017353:Gene Deletion; D005938:Glucocorticoids / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D020671:Posterior Horn Cells / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D013312:Stress, Physiological; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D005938:Glucocorticoids; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5