Analgesia through FKBP51 inhibition at disease onset confers lasting relief from sensory and emotional chronic pain symptoms

TY - JOUR

T1 - Analgesia through FKBP51 inhibition at disease onset confers lasting relief from sensory and emotional chronic pain symptoms

AU - Hestehave, Sara

AU - Florea, Roxana

AU - Singleton, Samuel

AU - Fedorec, Alex J H

AU - Caxaria, Sara

AU - Morgan, Oakley B

AU - Kopp, Katharina Tatjana

AU - Brown, Laurence A

AU - Heymann, Tim

AU - Sikandar, Shafaq

AU - Hausch, Felix

AU - Peirson, Stuart N

AU - Géranton, Sandrine M

N1 - Copyright © 2025 the Author(s).

PY - 2025/11/4

Y1 - 2025/11/4

N2 - Chronic pain affects 20 to 30% of the population and imposes a significant socioeconomic burden as it is often accompanied by substantial emotional comorbidities such as anxiety and depression. Yet, the mechanisms underlying the interactions between the sensory and emotional aspects of chronic pain remain poorly understood. Here, we investigated the role of FKBP51, a regulator of the stress response, in mediating both sensory and emotional symptoms of chronic pain. Inhibition of FKBP51, via genetic deletion or pharmacological blockade, in persistent joint pain reduced fast-onset sensory, functional and activity-related symptoms, as well as late anxio-depressive comorbidities. FKBP51 inhibition after the establishment of the hypersensitive state provided only temporary symptoms relief, while acute inhibition at disease onset protected from the full development of sensory and anxio-depressive symptoms for up to 6 mo. Our results also indicated that early pain symptoms could predict the late sensory and emotional outcomes of chronic pain. RNA sequencing of spinal cord tissue revealed that late FKBP51 inhibition transiently altered nociceptive genes associated with mechanical hypersensitivity. In contrast, early inhibition persistently downregulated the Naaa gene, a key regulator of the transition to chronic pain, and reorganized spinal cilia. Our results indicate that early FKBP51 inhibition after injury can persistently reduce chronic pain and prevent the onset of associated emotional comorbidities by modulating critical spinal neurobiological pathways that play pivotal roles in the transition to chronic pain.

AB - Chronic pain affects 20 to 30% of the population and imposes a significant socioeconomic burden as it is often accompanied by substantial emotional comorbidities such as anxiety and depression. Yet, the mechanisms underlying the interactions between the sensory and emotional aspects of chronic pain remain poorly understood. Here, we investigated the role of FKBP51, a regulator of the stress response, in mediating both sensory and emotional symptoms of chronic pain. Inhibition of FKBP51, via genetic deletion or pharmacological blockade, in persistent joint pain reduced fast-onset sensory, functional and activity-related symptoms, as well as late anxio-depressive comorbidities. FKBP51 inhibition after the establishment of the hypersensitive state provided only temporary symptoms relief, while acute inhibition at disease onset protected from the full development of sensory and anxio-depressive symptoms for up to 6 mo. Our results also indicated that early pain symptoms could predict the late sensory and emotional outcomes of chronic pain. RNA sequencing of spinal cord tissue revealed that late FKBP51 inhibition transiently altered nociceptive genes associated with mechanical hypersensitivity. In contrast, early inhibition persistently downregulated the Naaa gene, a key regulator of the transition to chronic pain, and reorganized spinal cilia. Our results indicate that early FKBP51 inhibition after injury can persistently reduce chronic pain and prevent the onset of associated emotional comorbidities by modulating critical spinal neurobiological pathways that play pivotal roles in the transition to chronic pain.

KW - Tacrolimus Binding Proteins/antagonists & inhibitors

KW - Chronic Pain/drug therapy

KW - Animals

KW - Mice

KW - Male

KW - Analgesia/methods

KW - Depression

KW - Emotions

KW - Anxiety

KW - Mice, Inbred C57BL

KW - Humans

KW - Spinal Cord/metabolism

KW - stress

KW - chronic pain

KW - emotional comorbidities

KW - FKBP51

UR - https://www.scopus.com/pages/publications/105020481107

U2 - 10.1073/pnas.2517405122

DO - 10.1073/pnas.2517405122

M3 - Article

C2 - 41166420

SN - 0027-8424

VL - 122

SP - 1

EP - 12

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 44

M1 - e2517405122

ER -