{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:44:47Z","timestamp":1788345887890,"version":"build-2803163510"},"reference-count":57,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2012,1,1]],"date-time":"2012-01-01T00:00:00Z","timestamp":1325376000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Mol Pain"],"published-print":{"date-parts":[[2012,1,1]]},"abstract":"<jats:sec><jats:title>Background:<\/jats:title><jats:p> Distal limb fracture in man can induce a complex regional pain syndrome (CRPS) with pain, warmth, edema, and cutaneous inflammation. In the present study substance P (SP, Tac1<jats:sup>\u2212\/\u2212<\/jats:sup>) and CGRP receptor (RAMP1<jats:sup>\u2212\/\u2212<\/jats:sup>) deficient mice were used to investigate the contribution of neuropeptide signaling to CRPS-like changes in a tibia fracture mouse model. Wildtype, Tac1<jats:sup>\u2212\/\u2212<\/jats:sup>, and RAMP1<jats:sup>\u2212\/\u2212<\/jats:sup> mice underwent tibia fracture and casting for 3 weeks, then the cast was removed and hindpaw mechanical allodynia, unweighting, warmth, and edema were tested over time. Hindpaw skin was collected at 3 weeks post-fracture for immunoassay and femurs were collected for micro-CT analysis. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p> Wildtype mice developed hindpaw allodynia, unweighting, warmth, and edema at 3 weeks post-fracture, but in the Tac1<jats:sup>\u2212\/\u2212<\/jats:sup> fracture mice allodynia and unweighting were attenuated and there was no warmth and edema. RAMP1<jats:sup>\u2212\/\u2212<\/jats:sup> fracture mice had a similar presentation, except there was no reduction in hindpaw edema. Hindpaw skin TNF\u03b1, IL-1\u03b2, IL-6 and NGF levels were up-regulated in wildtype fracture mice at 3 weeks post-fracture, but in the Tac1<jats:sup>\u2212\/\u2212<\/jats:sup> and RAMP1<jats:sup>\u2212\/\u2212<\/jats:sup> fracture mice only IL-6 was increased. The epidermal keratinocytes were the cellular source for these inflammatory mediators. An IL-6 receptor antagonist partially reversed post-fracture pain behaviors in wildtype mice. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions:<\/jats:title><jats:p> In conclusion, both SP and CGRP are critical neuropeptide mediators for the pain behaviors, vascular abnormalities, and up-regulated innate immune responses observed in the fracture hindlimb. We postulate that the residual pain behaviors observed in the Tac1<jats:sup>\u2212\/\u2212<\/jats:sup> and RAMP1<jats:sup>\u2212\/\u2212<\/jats:sup> fracture mice are attributable to the increased IL-6 levels observed in the hindpaw skin after fracture. <\/jats:p><\/jats:sec>","DOI":"10.1186\/1744-8069-8-85","type":"journal-article","created":{"date-parts":[[2012,11,28]],"date-time":"2012-11-28T21:27:17Z","timestamp":1354138037000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":65,"title":["Neuropeptide Deficient Mice Have Attenuated Nociceptive, Vascular, and Inflammatory Changes in a Tibia Fracture Model of Complex Regional Pain Syndrome"],"prefix":"10.1177","volume":"8","author":[{"given":"Tian-Zhi","family":"Guo","sequence":"first","affiliation":[{"name":"Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, 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