Tags

Type your tag names separated by a space and hit enter

Duration of Reduction in Enduring Stress-Induced Hyperalgesia Via FKBP51 Inhibition Depends on Timing of Administration Relative to Traumatic Stress Exposure.
J Pain. 2022 07; 23(7):1256-1267.JP

Abstract

Chronic pain development is a frequent outcome of severe stressor exposure, with or without tissue injury. Enduring stress-induced hyperalgesia (ESIH) is believed to play a central role, but the precise mechanisms mediating the development of chronic post-traumatic pain, and the time-dependency of these mechanisms, remain poorly understood. Clinical and preclinical data suggest that the inhibition of FK506-binding protein 51 (FKBP51), a key stress system regulator, might prevent ESIH. We evaluated whether peritraumatic inhibition of FKBP51 in an animal model of traumatic stress exposure, the single prolonged stress (SPS) model, reversed ESIH evaluated via daily mechanical von Frey testing. FKBP51 inhibition was achieved using SAFit2, a potent and specific small molecule inhibitor of FKBP51, administered to male and female Sprague-Dawley rats via intraperitoneal injection. To assess timing effects, FKBP51 was administered at different times relative to stress (SPS) exposure. SAFit2 administration immediately after SPS produced a complete reversal in ESIH lasting >7 days. In contrast, SAFit2 administration 72 hours following SPS produced only temporary hyperalgesia reversal, and administration 120h following SPS had no effect. Similarly, animals undergoing SPS together with tissue injury (plantar incision) receiving SAFit2 immediately post-surgery developed acute hyperalgesia but recovered by 4 days and did not develop ESIH. These data suggest that: 1) FKBP51 plays an important, time-dependent role in ESIH pathogenesis, 2) time windows of opportunity may exist to prevent ESIH via FKBP51 inhibition after traumatic stress, with or without tissue injury, and 3) the use of inhibitors of specific pathways may provide new insights into chronic post-traumatic pain development. PERSPECTIVE: The current work adds to a growing body of literature indicating that FKBP51 inhibition is a highly promising potential treatment strategy for reducing hyperalgesia. In the case of post-traumatic chronic pain, we show that such a treatment strategy would be particularly impactful if administered early after traumatic stress exposure.

Authors+Show Affiliations

Department of Anesthesiology, University of North Carolina, Chapel Hill, North Carolina; Institute for Trauma Recovery, University of North Carolina, Chapel Hill, North Carolina.Department of Anesthesiology, University of North Carolina, Chapel Hill, North Carolina; Institute for Trauma Recovery, University of North Carolina, Chapel Hill, North Carolina; Department of Emergency Medicine, University of North Carolina, Chapel Hill, North Carolina.Department of Anesthesiology, University of North Carolina, Chapel Hill, North Carolina; Institute for Trauma Recovery, University of North Carolina, Chapel Hill, North Carolina.Department of Anesthesiology, University of North Carolina, Chapel Hill, North Carolina; Institute for Trauma Recovery, University of North Carolina, Chapel Hill, North Carolina.Department of Chemistry and Biochemistry, Technical University Darmstadt, Darmstadt, Germany.Department of Chemistry and Biochemistry, Technical University Darmstadt, Darmstadt, Germany.Department of Anesthesiology, University of North Carolina, Chapel Hill, North Carolina; Institute for Trauma Recovery, University of North Carolina, Chapel Hill, North Carolina. Electronic address: sarah_linnstaedt@med.unc.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

35296422

Citation

Wanstrath, Britannia J., et al. "Duration of Reduction in Enduring Stress-Induced Hyperalgesia Via FKBP51 Inhibition Depends On Timing of Administration Relative to Traumatic Stress Exposure." The Journal of Pain, vol. 23, no. 7, 2022, pp. 1256-1267.
Wanstrath BJ, McLean SA, Zhao Y, et al. Duration of Reduction in Enduring Stress-Induced Hyperalgesia Via FKBP51 Inhibition Depends on Timing of Administration Relative to Traumatic Stress Exposure. J Pain. 2022;23(7):1256-1267.
Wanstrath, B. J., McLean, S. A., Zhao, Y., Mickelson, J., Bauder, M., Hausch, F., & Linnstaedt, S. D. (2022). Duration of Reduction in Enduring Stress-Induced Hyperalgesia Via FKBP51 Inhibition Depends on Timing of Administration Relative to Traumatic Stress Exposure. The Journal of Pain, 23(7), 1256-1267. https://doi.org/10.1016/j.jpain.2022.02.007
Wanstrath BJ, et al. Duration of Reduction in Enduring Stress-Induced Hyperalgesia Via FKBP51 Inhibition Depends On Timing of Administration Relative to Traumatic Stress Exposure. J Pain. 2022;23(7):1256-1267. PubMed PMID: 35296422.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Duration of Reduction in Enduring Stress-Induced Hyperalgesia Via FKBP51 Inhibition Depends on Timing of Administration Relative to Traumatic Stress Exposure. AU - Wanstrath,Britannia J, AU - McLean,Samuel A, AU - Zhao,Ying, AU - Mickelson,Jacqueline, AU - Bauder,Michael, AU - Hausch,Felix, AU - Linnstaedt,Sarah D, Y1 - 2022/03/14/ PY - 2021/08/09/received PY - 2022/01/31/revised PY - 2022/02/14/accepted PY - 2023/07/01/pmc-release PY - 2022/3/18/pubmed PY - 2022/7/14/medline PY - 2022/3/17/entrez KW - Chronic pain KW - FKBP51 KW - PTSD KW - SAFit2 KW - rats KW - stress KW - tissue injury SP - 1256 EP - 1267 JF - The journal of pain JO - J Pain VL - 23 IS - 7 N2 - Chronic pain development is a frequent outcome of severe stressor exposure, with or without tissue injury. Enduring stress-induced hyperalgesia (ESIH) is believed to play a central role, but the precise mechanisms mediating the development of chronic post-traumatic pain, and the time-dependency of these mechanisms, remain poorly understood. Clinical and preclinical data suggest that the inhibition of FK506-binding protein 51 (FKBP51), a key stress system regulator, might prevent ESIH. We evaluated whether peritraumatic inhibition of FKBP51 in an animal model of traumatic stress exposure, the single prolonged stress (SPS) model, reversed ESIH evaluated via daily mechanical von Frey testing. FKBP51 inhibition was achieved using SAFit2, a potent and specific small molecule inhibitor of FKBP51, administered to male and female Sprague-Dawley rats via intraperitoneal injection. To assess timing effects, FKBP51 was administered at different times relative to stress (SPS) exposure. SAFit2 administration immediately after SPS produced a complete reversal in ESIH lasting >7 days. In contrast, SAFit2 administration 72 hours following SPS produced only temporary hyperalgesia reversal, and administration 120h following SPS had no effect. Similarly, animals undergoing SPS together with tissue injury (plantar incision) receiving SAFit2 immediately post-surgery developed acute hyperalgesia but recovered by 4 days and did not develop ESIH. These data suggest that: 1) FKBP51 plays an important, time-dependent role in ESIH pathogenesis, 2) time windows of opportunity may exist to prevent ESIH via FKBP51 inhibition after traumatic stress, with or without tissue injury, and 3) the use of inhibitors of specific pathways may provide new insights into chronic post-traumatic pain development. PERSPECTIVE: The current work adds to a growing body of literature indicating that FKBP51 inhibition is a highly promising potential treatment strategy for reducing hyperalgesia. In the case of post-traumatic chronic pain, we show that such a treatment strategy would be particularly impactful if administered early after traumatic stress exposure. SN - 1528-8447 UR - https://www.unboundmedicine.com/medline/citation/35296422/Duration_of_Reduction_in_Enduring_Stress_Induced_Hyperalgesia_Via_FKBP51_Inhibition_Depends_on_Timing_of_Administration_Relative_to_Traumatic_Stress_Exposure_ DB - PRIME DP - Unbound Medicine ER -