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The primary endogenous ligands for DOR are enkephalins and their levels can be increased by pharmacological inhibition of enkephalinases; however, it is not clear whether enkephalinase inhibition can be efficacious in preclinical migraine models through activation of DOR or whether other opioid receptors might be involved. Further, it is not clear whether opioid receptors in the central nervous system are necessary for these effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study used a model of repetitive restraint stress in mice that induces periorbital hypersensitivity and priming to the nitric oxide donor sodium nitroprusside (SNP; 0.1\u2009mg\/kg). Von Frey filaments were used to measure periorbital mechanical thresholds and grimace scores were evaluated by observing mouse facial features. Animals were treated with the dual enkephalinase inhibitor (DENKI) PL37.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>On day two post\u2010stress, PL37 given to mice via either intravenous injection (10\u2009mg\/kg) or oral gavage (20\u2009mg\/kg) significantly attenuated stress\u2010induced periorbital hypersensitivity and facial grimace responses. Additionally, both intravenous (10\u2009mg\/kg) and oral gavage (20\u2009mg\/kg) of PL37 prior to SNP (0.1\u2009mg\/kg) administration on day 14 post\u2010stress significantly reduced SNP\u2010induced facial hypersensitivity. Injection of the DOR antagonist naltrindole (0.1\u2009mg\/kg) but not the mu\u2010opioid receptor antagonist CTAP (1\u2009mg\/kg) prior to PL37 treatment blocked the effects. Finally, pretreatment of mice with the peripherally restricted opioid receptor antagonist naloxone methiodide (5\u2009mg\/kg) blocked the effects of PL37.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data demonstrate that inhibiting enkephalinases, and thus protecting enkephalins from degradation, attenuates stress\u2010induced migraine\u2010like behavior via activation of peripheral DOR. Peripheral targeting of endogenous opioid signaling may be an effective therapeutic strategy for migraine.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/head.14517","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T03:19:58Z","timestamp":1684120798000},"page":"621-633","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Efficacy of dual\n                    <scp>enkephalinase<\/scp>\n                    inhibition in a preclinical migraine model is mediated by activation of peripheral delta opioid receptors"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9991-4069","authenticated-orcid":false,"given":"Hao\u2010Ruei","family":"Mei","sequence":"first","affiliation":[{"name":"Department of Neuroscience University of Texas at Dallas  Richardson Texas USA"},{"name":"School of Behavioral and Brain Science, Center for Advanced Pain 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