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Although analgesics are routinely used in laboratory animal studies, their effects on neuroendocrine and neuropathological responses to blast remain insufficiently understood. This study investigated how preinjury administration of buprenorphine (BUP) or meloxicam (MEL) modulates hypothalamic\u2013pituitary\u2013adrenal axis activation, axonal injury, tau phosphorylation, and astroglial responses following blast exposure. Male Sprague Dawley rats were assigned to sham, blast, blast + MEL, or blast + BUP groups and subjected to two tightly coupled \u223c19-psi blast waves using an advanced blast simulator. Serum corticosterone and adrenocorticotropic hormone (ACTH) levels and cerebrospinal fluid (CSF) levels of phosphorylated neurofilament heavy chain (pNFH) were quantified on days 1 and 30, alongside regional (cortex, hippocampus, cerebellum, brainstem) protein expression of pNFH, pTau (Ser396), and glial fibrillary acidic protein (GFAP). Repeated blast exposure caused strong acute elevations in corticosterone, ACTH, and pNFH. BUP suppressed both hormones, whereas MEL selectively reduced ACTH. Both analgesics significantly attenuated acute increases in pNFH, while MEL further mitigated chronic regional elevations in pNFH and GFAP, indicating stronger long-term suppression of axonal and astroglial pathology postblast. Tau hyperphosphorylation was predominantly an acute event, with MEL producing modest region-specific reduction. Region-dependent analyses revealed persistent cortical and brainstem axonal injury, biphasic hippocampal responses, and minimal cerebellar involvement. By day 30, endocrine and CSF biomarkers showed biochemical normalization in analgesic-treated animals but remained elevated in untreated blast-exposed rats. Our findings indicate that routine laboratory analgesics substantially modulate key biomarkers of blast-induced neurotrauma, introducing methodological and interpretive confounds that can impact cross-study reproducibility. Thus, the study should be interpreted primarily as evidence of analgesic-induced biomarker modulation rather than therapeutic neuroprotection.<\/jats:p>","DOI":"10.1177\/08977151261442479","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T07:41:56Z","timestamp":1776411716000},"page":"1856-1868","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Analgesic Modulation of Neuroendocrine and Region-Specific Neuropathological Responses Following Blast-Induced Traumatic Brain Injury in Rats"],"prefix":"10.1177","volume":"43","author":[{"given":"Rex Jeya Rajkumar","family":"Samdavid Thanapaul","sequence":"first","affiliation":[{"name":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, 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