{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:14:54Z","timestamp":1790648094240,"version":"4.1.0"},"reference-count":77,"publisher":"SAGE Publications","issue":"8","license":[{"start":{"date-parts":[[2017,4,4]],"date-time":"2017-04-04T00:00:00Z","timestamp":1491264000000},"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":["Cephalalgia"],"published-print":{"date-parts":[[2017,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Stress is the most commonly reported migraine trigger. Dynorphin, an endogenous opioid peptide acting preferentially at kappa opioid receptors (KORs), is a key mediator of stress responses. The aim of this study was to use an injury-free rat model of functional cephalic pain with features of migraine and medication overuse headache (MOH) to test the possible preventive benefit of KOR blockade on stress-induced cephalic pain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Following sumatriptan priming to model MOH, rats were hyper-responsive to environmental stress, demonstrating delayed cephalic and extracephalic allodynia and increased levels of CGRP in the jugular blood, consistent with commonly observed clinical outcomes during migraine. Nor-binaltorphimine (nor-BNI), a long-acting KOR antagonist or CYM51317, a novel short-acting KOR antagonist, were given systemically either during sumatriptan priming or immediately before environmental stress challenge. The effects of KOR blockade in the amygdala on stress-induced allodynia was determined by administration of nor-BNI into the right or left central nucleus of the amygdala (CeA).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>KOR blockade prevented both stress-induced allodynia and increased plasma CGRP. Stress increased dynorphin content and phosphorylated KOR in both the left and right CeA in sumatriptan-primed rats. However, KOR blockade only in the right CeA prevented stress-induced cephalic allodynia as well as extracephalic allodynia, measured in either the right or left hindpaws. U69,593, a KOR agonist, given into the right, but not the left, CeA, produced allodynia selectively in sumatriptan-primed rats. Both stress and U69,593-induced allodynia were prevented by right CeA U0126, a mitogen-activated protein kinase inhibitor, presumably acting downstream of KOR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data reveal a novel lateralized KOR circuit that mediated stress-induced cutaneous allodynia and increased plasma CGRP in an injury-free model of functional cephalic pain with features of migraine and medication overuse headache. Selective, small molecule, orally available, and reversible KOR antagonists are currently in development and may represent a novel class of preventive therapeutics for migraine.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/0333102417702120","type":"journal-article","created":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T02:42:41Z","timestamp":1491360161000},"page":"780-794","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":86,"title":["Kappa opioid receptor antagonists: A possible new class of therapeutics for migraine prevention"],"prefix":"10.1177","volume":"37","author":[{"given":"Jennifer Y","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"De Felice","sequence":"additional","affiliation":[{"name":"School of Clinical Dentistry, University of Sheffield, Sheffield, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline M","family":"Kopruszinski","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Biological Sciences Section, Federal University of Parana, Curitiba, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Eyde","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"LaVigne","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, 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":"Pablo","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Goshima","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ossipov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"King","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Osteopathic Medicine, Center for Excellence in the Neurosciences, University of New England, Biddeford, ME, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M","family":"Streicher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edita","family":"Navratilova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Dodick","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Phoenix, AZ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugh","family":"Rosen","sequence":"additional","affiliation":[{"name":"Scripps Research Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ed","family":"Roberts","sequence":"additional","affiliation":[{"name":"Scripps Research Institute, La Jolla, CA, 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, Phoenix, AZ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2017,4,4]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","unstructured":"GBD 2015 Disease and Injury Incidence and Prevalence Collaborators Vos T Allen C Arora M et al. 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