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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. 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.
