Research ArticlePain

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

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Science Translational Medicine  10 Feb 2016:
Vol. 8, Issue 325, pp. 325ra19
DOI: 10.1126/scitranslmed.aab3376

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A key to chronic pain

Our treatment tools are distressingly poor for alleviating long-lasting, debilitating pain, so new ideas are welcome. Maiarù et al. now find that inhibition of spinal cord FKBP51—a stress-related protein involved with glucocorticoid signaling—can curtail the development of chronic pain in animal models. More important for clinical application, siRNA inhibition or a newly developed FKBP51 inhibitor, SAFit2, can interrupt a preexisting chronic pain state. The authors also amass evidence from their mouse models that FKBP51 acts on chronic pain via the glucocorticoid signaling pathway. Variation in the human gene FKBP51 alters pain severity after trauma, lending confidence that drugs like SAFit2 may help patients suffering from chronic pain.


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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