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

Chronic pain affects 20-30% of the population and imposes a significant socio-economic 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 months. 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. Overall design: RNA Sequencing (NextSeq 500, Illumina) of mouse lumbar (L4-l6) spinal cord on day 30 after injection of sodium iodoacetate (MIA; 1 mg) into the knee joint. The aim of the study was to establish the mechanisms conferring anti-allodynia by the FKBP5 inhibitor SAFit2 in the MIA model of osteoarthritis and the influence of time of SAFit2 administration. Early samples were injected with vesicular phospholipid gel (VPG)-SAFit2 on days -3 before MIA and day 4 after MIA whilst late samples were injected on days 20 and 27 after MIA. Matched vehicle injections (VPG) occured at the same time points.