{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:53:54Z","timestamp":1792785234296,"version":"4.5.0"},"reference-count":58,"publisher":"National Academy of Sciences","issue":"44","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012041","name":"Versus Arthritis","doi-asserted-by":"publisher","award":["21972"],"award-info":[{"award-number":["21972"]}],"id":[{"id":"10.13039\/501100012041","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Advanced pain discovery platform","award":["MR\/W002566\/1"],"award-info":[{"award-number":["MR\/W002566\/1"]}]},{"DOI":"10.13039\/501100000268","name":"UKRI | Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/X002357\/1"],"award-info":[{"award-number":["BB\/X002357\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic toggle=\"yes\">Naaa<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2517405122","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T17:43:07Z","timestamp":1761846187000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["Analgesia through FKBP51 inhibition at disease onset confers lasting relief from sensory and emotional chronic pain symptoms"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1837-521X","authenticated-orcid":false,"given":"Sara","family":"Hestehave","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology, University College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5095-2920","authenticated-orcid":false,"given":"Roxana","family":"Florea","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, University College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Singleton","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, School of Medicine, University of Dundee","place":["Dundee, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0165-1705","authenticated-orcid":false,"given":"Alex J. 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Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8116-4100","authenticated-orcid":false,"given":"Laurence A.","family":"Brown","sequence":"additional","affiliation":[{"name":"Research Support Team, Information Technology Services, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Heymann","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Institute of Organic Chemistry and Biochemistry, Technical University Darmstadt","place":["Darmstadt, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6010-5205","authenticated-orcid":false,"given":"Shafaq","family":"Sikandar","sequence":"additional","affiliation":[{"name":"Experimental Medicine and 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Hestehave Analgesia through FKBP51 inhibition at disease onset confers lasting relief from sensory and emotional chronic pain symptoms. GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE293520. 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