MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior: Possible involvement of the GluN2B receptor

Hai Quyen Tran, Yoon Hee Chung, Eun Joo Shin, The Vinh Tran, Ji Hoon Jeong, Choon Gon Jang, Seung Yeol Nah, Kiyofumi Yamada, Toshitaka Nabeshima, Hyoung Chun Kim

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Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well-documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80 mg/kg), Sprague–Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N-methyl-D-aspartate (NMDA) receptor subunits (GluN1 < GluN2A < GluN2B), c-Fos and pro-apoptotic factors (Bax and cleaved caspase-3) were upregulated by DM treatment; while levels of anti-apoptotic factors (Bcl-2 and Bcl-xL) were downregulated. Consistently, DM also induced ultrastructural degeneration in the hippocampus. A non-competitive NMDA receptor antagonist, MK-801, attenuated these effects of high-dose DM, whereas an opioid antagonist, naloxone, did not affect DM-induced neurotoxicity. Moreover, pretreatment with a highly specific GluN2B subunit inhibitor, traxoprodil, was selectively effective in preventing DM-induced c-Fos expression and apoptotic changes. These results suggest that high-dose DM produces convulsive behaviors by activating GluN2B/NMDA signaling that leads to pro-apoptotic changes.

Original languageEnglish
Pages (from-to)158-166
Number of pages9
JournalToxicology and Applied Pharmacology
Publication statusPublished - 01-11-2017


All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

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