{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T18:13:20Z","timestamp":1793384000019,"version":"4.5.0"},"reference-count":83,"publisher":"SAGE Publications","issue":"14","license":[{"start":{"date-parts":[[2019,9,24]],"date-time":"2019-09-24T00:00:00Z","timestamp":1569283200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100006259","name":"Teva Pharmaceutical Industries","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006259","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Cephalalgia"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Acute and persistent post-traumatic headache are often debilitating consequences of traumatic brain injury. Underlying physiological mechanisms of post-traumatic headache and its persistence remain unknown, and there are currently no approved therapies for these conditions. Post-traumatic headache often presents with a migraine-like phenotype. As calcitonin-gene related peptide promotes migraine headache, we explored the efficacy and timing of intervention with an anti- calcitonin-gene related peptide monoclonal antibody in novel preclinical models of acute post-traumatic headache and persistent post-traumatic headache following a mild traumatic brain injury event in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Male, C57Bl\/6\u2009J mice received a sham procedure or mild traumatic brain injury resulting from a weight drop that allowed free head rotation while under minimal anesthesia. Periorbital and hindpaw tactile stimulation were used to assess mild traumatic brain injury-induced cutaneous allodynia. Two weeks after the injury, mice were challenged with stress, a common aggravator of migraine and post-traumatic headache, by exposure to bright lights (i.e. bright light stress) and cutaneous allodynia was measured hourly for 5 hours. A murine anti- calcitonin-gene related peptide monoclonal antibody was administered after mild traumatic brain injury at different time points to allow evaluation of the consequences of either early and sustained calcitonin-gene related peptide sequestration or late administration only prior to bright light stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Mice with mild traumatic brain injury, but not a sham procedure, exhibited both periorbital and hindpaw cutaneous allodynia that resolved by post-injury day 13. Following resolution of injury-induced cutaneous allodynia, exposure to bright light stress re-instated periorbital and hindpaw cutaneous allodynia in injured, but not sham mice. Repeated administration of anti-calcitonin-gene related peptide monoclonal antibody at 2 hours, 7 and 14 days post mild traumatic brain injury significantly attenuated the expression of cutaneous allodynia when evaluated over the 14-day post injury time course and also prevented bright light stress-induced cutaneous allodynia in injured mice. Administration of anti-calcitonin-gene related peptide monoclonal antibody only at 2 hours and 7 days after mild traumatic brain injury blocked injury-induced cutaneous allodynia and partially prevented bright light stress-induced cutaneous allodynia. A single administration of anti-calcitonin-gene related peptide monoclonal antibody after the resolution of the peak injury-induced cutaneous allodynia, but prior to bright light stress challenge, did not prevent bright light stress-induced cutaneous allodynia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We used a clinically relevant mild traumatic brain injury event in mice along with a provocative stimulus as novel models of acute post-traumatic headache and persistent post-traumatic headache. Following mild traumatic brain injury, mice demonstrated transient periorbital and hindpaw cutaneous allodynia suggestive of post-traumatic headache-related pain and establishment of central sensitization. Following resolution of injury-induced cutaneous allodynia, exposure to bright light stress re-established cutaneous allodynia, suggestive of persistent post-traumatic headache-related pain. Continuous early sequestration of calcitonin-gene related peptide prevented both acute post-traumatic headache and persistent post-traumatic headache. In contrast, delayed anti-calcitonin-gene related peptide monoclonal antibody treatment following establishment of central sensitization was ineffective in preventing persistent post-traumatic headache. These observations suggest that mechanisms involving calcitonin-gene related peptide underlie the expression of acute post-traumatic headache, and drive the development of central sensitization, increasing vulnerability to headache triggers and promoting persistent post-traumatic headache. Early and continuous calcitonin-gene related peptide blockade following mild traumatic brain injury may represent a viable treatment option for post-traumatic headache and for the prevention of post-traumatic headache persistence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abbreviations<\/jats:title>\n                    <jats:p>CA Cutaneous allodynia CGRP Calcitonin gene-related peptide mTBI Mild traumatic brain injury PTH Post-traumatic headache APTH Acute post-traumatic headache PPTH Persistent post-traumatic headache<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/0333102419877662","type":"journal-article","created":{"date-parts":[[2019,9,24]],"date-time":"2019-09-24T20:43:01Z","timestamp":1569357781000},"page":"1762-1775","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":99,"title":["CGRP-dependent and independent mechanisms of acute and persistent post-traumatic headache following mild traumatic brain injury in mice"],"prefix":"10.1177","volume":"39","author":[{"given":"Edita","family":"Navratilova","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Rau","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Scottsdale, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice","family":"Oyarzo","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Scottsdale, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Tien","sequence":"additional","affiliation":[{"name":"Teva Biologics, Redwood City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Mackenzie","sequence":"additional","affiliation":[{"name":"Teva Biologics, Redwood City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Stratton","sequence":"additional","affiliation":[{"name":"Teva Biologics, Redwood City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany","family":"Remeniuk","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd","family":"Schwedt","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Scottsdale, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trent","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Dodick","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Scottsdale, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Porreca","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA"},{"name":"Mayo Clinic, Scottsdale, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,9,24]]},"reference":[{"key":"bibr1-0333102419877662","doi-asserted-by":"publisher","DOI":"10.1177\/0333102413499645"},{"key":"bibr2-0333102419877662","first-page":"549","volume":"62","author":"Centers for Disease Control and Prevention (CDC)","year":"2013","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"bibr3-0333102419877662","doi-asserted-by":"publisher","DOI":"10.1097\/00001199-200609000-00001"},{"key":"bibr4-0333102419877662","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-52892-6.00001-5"},{"key":"bibr5-0333102419877662","doi-asserted-by":"publisher","DOI":"10.1080\/16501960410023732"},{"key":"bibr6-0333102419877662","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70262-4"},{"key":"bibr7-0333102419877662","unstructured":"Centers for Disease Control and Prevention (CDC). 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