Acute and early stress axis modulation in joint disease permanently reduces pain and emotional comorbidities

Chronic secondary musculoskeletal pain affects 20-30% of the population and includes sensory disturbances and emotional comorbidities, such as anxiety and depression, which reduce quality of life. We monitored a pre-clinical model of persistent joint pain for 6 months and found that sensory and functional changes were immediate while anxio-depressive comorbidities appeared from 3 months onwards. Modulating the stress axis via genetic deletion or pharmacological blockade of the stress driver FKBP51 reduced both sensory and emotional symptoms, including injury-induced disruptions in sleep and activity patterns, and did not worsen joint damage. FKBP51 pharmacological blockade after the establishment of the hypersensitive state provided temporary relief while acute inhibition at disease onset, when sensory and affective responses were most severe, provided at least 6 months of pain relief and reduced or prevented late anxiety- and depressive-like behavior. RNA sequencing suggested that FKBP51 inhibition at disease onset downregulated the Naaa gene in the superficial dorsal horn, a key regulator of the transition to chronic pain, and reorganized spinal cilia. Our findings suggest that acute and early, but not late, FKBP51 targeting can offer permanent relief from chronic pain and its emotional effects, highlighting the importance for fast therapeutic intervention.