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Studies have demonstrated the impact of methadone on seizure susceptibility. This study investigated the modulatory impacts of acute and subchronic (three times daily for 5 days) intraperitoneal methadone treatment on pentylenetetrazole\u2010induced clonic seizure threshold (CST) in mice, as well as the involvement of the nitric oxide, <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate (NMDA), and \u00b5\u2010opioid pathways. Acute administration of different doses of methadone (0.1, 0.3, 1, and 3\u00a0mg\/kg) 45\u00a0min before CST significantly decreased the seizure threshold. Additionally, pretreatment with noneffective doses of an opioid receptor antagonist (naltrexone) and NMDA receptor antagonists (ketamine and MK\u2010801) inhibited methadone's proconvulsive activity in the acute phase, while <jats:sc>l<\/jats:sc>\u2010NAME (a nonspecific nitric oxide synthase (NOS) inhibitor) did not affect that activity. In the subchronic phase, methadone (3\u00a0mg\/kg) demonstrated an anticonvulsive effect. Although subchronic pretreatment with noneffective doses of <jats:sc>l<\/jats:sc>\u2010NAME and 7\u2010nitroindazole (a specific neuronal NOS inhibitor) reversed methadone's anticonvulsive activity, aminoguanidine (a specific inducible NOS inhibitor), naltrexone, MK\u2010801, and ketamine did not change methadone's anticonvulsive characteristic. Our results suggest that NMDA and \u00b5\u2010opioid receptors may be involved in methadone's proconvulsive activity in the acute phase, while methadone's anticonvulsive activity may be modulated by neuronal NOS in the subchronic phase.<\/jats:p>","DOI":"10.1111\/nyas.14043","type":"journal-article","created":{"date-parts":[[2019,4,8]],"date-time":"2019-04-08T04:12:58Z","timestamp":1554696778000},"page":"25-35","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Methadone's effects on pentylenetetrazole\u2010induced seizure threshold in mice: NMDA\/opioid receptors and nitric oxide signaling"],"prefix":"10.1111","volume":"1449","author":[{"given":"Soheil","family":"Kazemi Roodsari","sequence":"first","affiliation":[{"name":"Experimental Medicine Research Center Tehran University of Medical Sciences  Tehran Iran"},{"name":"Department of Pharmacology, School of Medicine Tehran University of Medical Sciences  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erfan","family":"Bahramnejad","sequence":"additional","affiliation":[{"name":"Experimental Medicine Research Center Tehran University of Medical Sciences  Tehran Iran"},{"name":"Department of Pharmacology, School of Medicine Tehran University of Medical Sciences  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nastaran","family":"Rahimi","sequence":"additional","affiliation":[{"name":"Experimental Medicine Research Center Tehran University of Medical Sciences  Tehran Iran"},{"name":"Department of Pharmacology, School of Medicine Tehran University of Medical Sciences  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iraj","family":"Aghaei","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Neuroscience Research Center, Poursina Hospital Guilan University of Medical Sciences  Rasht Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad Reza","family":"Dehpour","sequence":"additional","affiliation":[{"name":"Experimental Medicine Research Center Tehran University of Medical Sciences  Tehran Iran"},{"name":"Department of Pharmacology, School of Medicine Tehran University of Medical Sciences  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,4,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1089\/109662102753641331"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0361-9230(02)00805-5"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyl207"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s001150050657"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(77)80523-4"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(84)90200-4"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2010.06.010"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-1211(01)00316-3"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2011.01.014"},{"key":"e_1_2_7_11_1","first-page":"8","article-title":"Nitric oxide\/cyclic guanosine monophosphate system in the spinal cord differentially modulates intracerebroventricularly administered morphine\u2010 and b\u2010endorphin\u2010induced antinociception in the mouse","volume":"274","author":"Xu J.Y.","year":"1995","journal-title":"J. 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