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However, the development of delta agonists is limited as some ligands have seizurogenic properties, which may be related to their ability to induce receptor internalization. While both pro\u2010 and non\u2010convulsant delta agonists can reduce migraine\u2010associated allodynia, only the proconvulsant agonist, SNC80, has been shown to decrease cortical spreading depression (CSD). It is unclear if the ability of delta agonists to modulate cortical activity is related to the same signaling mechanisms that produce proconvulsant effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The effects of the non\u2010convulsant delta agonist, KNT\u2010127, were examined. Repetitive CSD was induced in female C57BL6\/J (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a06\/group) mice by continuous application of KCl and the effect of KNT\u2010127\/vehicle (Veh) on both local field potentials and optical intrinsic signals was determined. To assess the effect of KNT\u2010127 on established chronic migraine\u2010associated pain, male and female C57BL6\/J mice were treated with nitroglycerin (NTG; 10\u00a0mg\/kg, ip) every other day for 9\u00a0days and tested with KNT\u2010127 (5\u00a0mg\/kg, sc) or Veh on day 10 (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a06\/group). DOR\u2010enhanced green fluorescent protein mice (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a04\/group) were used to confirm the internalization properties of KNT\u2010127 in the trigeminal ganglia, trigeminal nucleus caudalis, and somatosensory cortex.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      KNT\u2010127 inhibited CSD events (\n                      <jats:italic>t<\/jats:italic>\n                      <jats:sub>(10)<\/jats:sub>\n                      \u00a0=\u00a03.570,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.0051). In addition, this delta agonist also reversed established cephalic allodynia in the NTG model of chronic migraine (\n                      <jats:italic>F<\/jats:italic>\n                      <jats:sub>(1, 20)<\/jats:sub>\n                      \u00a0=\u00a012.80,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.01). Furthermore, KNT\u2010127 caused limited internalization of DOR in key migraine processing regions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study shows that the antimigraine effects of DOR agonists can be separated from their proconvulsant effects. This data provides valuable information for the continued development of delta agonists for the treatment of migraine.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/head.14019","type":"journal-article","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T15:22:10Z","timestamp":1608218530000},"page":"170-178","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["A non\u2010convulsant delta\u2010opioid receptor agonist, KNT\u2010127, reduces cortical spreading depression and nitroglycerin\u2010induced allodynia"],"prefix":"10.1111","volume":"61","author":[{"given":"Zachariah","family":"Bertels","sequence":"first","affiliation":[{"name":"Department of Psychiatry University of Illinois at Chicago Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0296-5055","authenticated-orcid":false,"given":"Wiktor 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