{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:24:34Z","timestamp":1787217874596,"version":"build-2736575974"},"reference-count":75,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pain is a common neurological manifestation of COVID\u201019, yet the mechanisms by which SARS\u2010CoV\u20102 spike protein fragments contribute to nociceptive processing remain poorly understood. We investigated whether spike\u2010derived peptides directly activate spinal neuroimmune pathways involved in pain signalling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Male C57BL\/6 mice received intrathecal administration of three synthetic SARS\u2010CoV\u20102 spike\u2010derived peptides (PSPD2001, PSPD2002 or PSPD2003) or saline. Mechanical nociception was assessed using the von Frey test. The involvement of spinal Toll\u2010like receptor 4 (TLR4), microglia and p38 MAPK\/NF\u2010\u03baB signalling was investigated using pharmacological antagonists, TLR4 knockout mice, RT\u2010qPCR, ELISA, immunofluorescence, CX3CR1\n                      <jats:sup>GFP\/+<\/jats:sup>\n                      mice, human C20 microglial cells and molecular dynamics simulations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All spike\u2010derived peptides induced mechanical nociception, with PSPD2003 producing the most pronounced response. PSPD2003 increased spinal TLR4 expression, elevated TNF\u2010\u03b1 and IL\u20106 levels and promoted activation of dorsal horn microglia, demonstrated by increased TMEM119\u2010 and CX3CR1\u2010positive cells. These nociceptive and neuroinflammatory effects were abolished by pharmacological inhibition of TLR4, microglia, p38 MAPK and NF\u2010\u03baB signalling, as well as in TLR4\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice, demonstrating that TLR4 signalling is essential for PSPD2003\u2010induced pain. PSPD2003 also induced a hypertrophic phenotype in human microglial cells, while molecular dynamics simulations supported a stable interaction with the TLR4\/MD\u20102 complex.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings identify a previously unrecognized neuroimmune mechanism whereby a SARS\u2010CoV\u20102 spike\u2010derived peptide triggers spinal nociception through TLR4\u2010dependent microglial activation and downstream p38 MAPK\/NF\u2010\u03baB signalling, highlighting the spinal TLR4\u2013microglia axis as a potential therapeutic target for COVID\u201019\u2010associated and post\u2010viral pain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>This study provides the first evidence that SARS\u2010CoV\u20102 spike\u2010derived peptides directly activate a spinal TLR4\u2010dependent neuroimmune pathway to induce nociception. By integrating behavioural, pharmacological, genetic, cellular and computational approaches, it identifies microglial activation and p38 MAPK\/NF\u2010\u03baB signalling as key mechanisms linking viral peptides to pain, providing a mechanistic framework for COVID\u201019\u2010 and post\u2010viral pain and supporting TLR4 as a potential therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejp.70343","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:32:09Z","timestamp":1785850329000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>SARS<\/scp>\n                    \u2010\n                    <scp>CoV<\/scp>\n                    \u20102 Spike Peptides Trigger Nociceptive Responses Through Spinal\n                    <scp>TLR4<\/scp>\n                    Pathways"],"prefix":"10.1002","volume":"30","author":[{"given":"Bruno 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