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

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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
Volume334
DOIs
Publication statusPublished - 01-11-2017

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Dextromethorphan
Dizocilpine Maleate
Naloxone
N-Methyl-D-Aspartate Receptors
Seizures
Levorphanol
Antitussive Agents
Narcotic Antagonists
N-Methylaspartate
Caspase 3
Isomers
Morphine
Opioid Analgesics
Rats
Hippocampus

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

Cite this

Tran, Hai Quyen ; Chung, Yoon Hee ; Shin, Eun Joo ; Tran, The Vinh ; Jeong, Ji Hoon ; Jang, Choon Gon ; Nah, Seung Yeol ; Yamada, Kiyofumi ; Nabeshima, Toshitaka ; Kim, Hyoung Chun. / MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior : Possible involvement of the GluN2B receptor. In: Toxicology and Applied Pharmacology. 2017 ; Vol. 334. pp. 158-166.
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abstract = "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.",
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MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior : Possible involvement of the GluN2B receptor. / Tran, Hai Quyen; Chung, Yoon Hee; Shin, Eun Joo; Tran, The Vinh; Jeong, Ji Hoon; Jang, Choon Gon; Nah, Seung Yeol; Yamada, Kiyofumi; Nabeshima, Toshitaka; Kim, Hyoung Chun.

In: Toxicology and Applied Pharmacology, Vol. 334, 01.11.2017, p. 158-166.

Research output: Contribution to journalArticle

TY - JOUR

T1 - MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior

T2 - Possible involvement of the GluN2B receptor

AU - Tran, Hai Quyen

AU - Chung, Yoon Hee

AU - Shin, Eun Joo

AU - Tran, The Vinh

AU - Jeong, Ji Hoon

AU - Jang, Choon Gon

AU - Nah, Seung Yeol

AU - Yamada, Kiyofumi

AU - Nabeshima, Toshitaka

AU - Kim, Hyoung Chun

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

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