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Understanding OA as both an inflammatory and neurological disease presents challenges for diagnosis and treatment, as no curative therapy is currently available. The neuroactive effects of OA pain on neuropeptide systems, particularly within the spinal cord, remain underexplored, impeding therapeutic advances. Mass spectrometry (MS) was employed to characterize the spinal cord peptidome in a validated rat model of OA pain. The peptidome was analyzed longitudinally over 84 days using the Montreal Induction of Rat Arthritis Testing (MI-RAT\u00a9; n = 20) model, compared to arthrotomic (Sham; n = 4) and healthy (Naive; n = 9) groups. Label-free peptidome profiling using liquid chromatography coupled with tandem MS (LC-MS\/MS) revealed dynamic changes in endogenous spinal peptides during OA progression, leading to the identification of 624 peptides derived from 29 prohormone precursors. The findings reveal substantial changes in peptide levels in the spinal cord, particularly involving neuropeptide substance P and peptides derived from proenkephalin, calcitonin gene-related peptide, and somatostatin. These results provide novel insights into the molecular mechanisms underlying OA-associated pain and identify potential targets for new therapeutic interventions in neurological pain conditions.<\/jats:p>\n                  <jats:p\/>","DOI":"10.1039\/d5mo00152h","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T12:43:26Z","timestamp":1761741806000},"page":"645-656","update-policy":"https:\/\/doi.org\/10.1039\/rsc_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Global spinal cord peptidome profiling in response to osteoarthritis in rats"],"prefix":"10.1093","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7955-9541","authenticated-orcid":false,"given":"Gaoyuan","family":"Lu","sequence":"first","affiliation":[{"name":"School of Pharmacy, University of Wisconsin-Madison a , Madison, WI 53705, USA lingjun.li@wisc.edu \u00a0 +1-608-262-5345 \u00a0 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