• Biomolecules & Therapeutics
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• 제12권4호
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• pp.198-201
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• 2004

This review focuses on finding neurochemical changes in physical dependence on butorphanol, a relatively potent mixed agonist-antagonist opioid analgesic agent that is five times more potent than morphine in antinociceptive effects. The chronic administration of butorphanol induces physical dependence. Withdrawal from such dependence can be reliably precipitated by administration of a narcotic antagonist, e.g., naloxone. Evidence for critical involvement of excitatory aminoacid (glutamate), opioid receptors, and phosphorylation of proteins in these phenomena is summarized.

• Archives of Pharmacal Research
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• 제25권3호
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• pp.349-356
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• 2002

The present study was performed to examine the effect of fangchinoline, a bis- benzylisoquinoline alkaloid, which exhibits the characteristics of a $Ca^{2+}$ channel blocker, on cyanide-induced neurotoxicity using cultured rat cerebellar granule neurons. NaCN produced a concentration-dependent reduction of cell viability, which was blocked by MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, verapamil, L-type$Ca^{2+}$channel blocker, and L-NAME, a nitric oxide synthase inhibitor. Pretreatment with fangchinoline over a concentration range of 0.1 to 10 $\mu$M significantly decreased the NaCN-induced neuronal cell death, glutamate release into medium, and elevation of $[Ca^{2+}]_i$ and oxidants generation. These results suggest that fangchinoline may mitigate the harmful effects of cyanide-induced neuronal cell death by interfering with $[Ca^{2+}]_i$influx, due to its function as a $Ca^{2+}$ channel blocker, and then by inhibiting glutamate release and oxidants generation.

• 한국한의학연구원논문집
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• 제4권1호통권4호
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• pp.99-114
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• 1998

The effect of herbal medicine on glutamate mediated neurotoxicity was studied in mouse neurons in primary culture. Immature cerebral cortex neurons (ED14) were maintained for up to 2 weeks in vitro, and we investigated the expression pattern of neuron differentiation and cytotoxicity of cell death, including LDH activity. Neuronal maturation initiated on day 7 and the susceptibility to glutamate-induced cell death was highly sensitive on Day 11 (Fig. 1). Thus, the exposure of the neurons to glutamate caused a dose$(0.1mM{\sim}1mM)$ and time$(4h{\sim}24h)$-dependent neurotoxicity(Fig. 4). Glutamate-induced neurodegeneration was prevented by Shipchondaebotang(SD), Yollyounggobondan(YG), Yugmijihwangwon(YJ) and the death of neurons exposed to glutamate was blocked by the NMDA receptor antagonist MK-801 (Fig. 5).

• International Journal of Oral Biology
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• 제32권2호
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• pp.59-65
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• 2007

It has been well known that excitatory amino acids, primarily glutamate, are involved in the transmission of nociception in pathological and physiological conditions in the spinal and brainstem level. Recently, peripheral glutamate also play a critical role in the peripheral nociceptive transmissions. The present study investigated the role of N-methyl-D-aspartic acid (NMDA) or non-NMDA ionotropic glutamate receptors in formalin-induced TMJ pain. Experiments were carried out on male Sprague-Dawley rats weighing 220-280 g. Intra-articular injection was performed under halothane anesthesia. Under anesthesia, AP-7 (10, $100\;{\mu}M$, $1\;mM/20\;{\mu}L$), a NMDA receptor antagonist, or CNQX disodium salt (0.5, 5, 50, $500\;{\mu}M/20\;{\mu}L$), a non-NMDA receptor antagonist, were administered intra-articularly 10 min prior to the application of 5% formalin. For each animal, the number of behavioral responses, such as rubbing and/or scratching the TMJ region, was recorded for nine successive 5-min intervals. Intra-articular pretreatment with 1 mM of AP-7 or $50\;{\mu}M$ CNQX significantly decreased the formalin-induced scratching behavioral responses during the second phase. Intra-articular pretreatment with $500\;{\mu}M$ of CNQX significantly decreased the formalin-induced scratching behavior during both the first and the second phase. These results indicate that the intra-articular administration of NMDA or non-NMDA receptor antagonists inhibit formalin-induced TMJ nociception, and peripheral ionotropic glutamate receptors may play an important role in the TMJ nociception.

• Journal of Ginseng Research
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• 제36권1호
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• pp.47-54
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• 2012

Korean red ginseng (KRG) has been used worldwide as a traditional medicine for the treatment of various reproductive diseases. Gonadotropin releasing hormone (GnRH) neurons are the fundamental regulators of pulsatile release of gonadotropin required for fertility. In this study, an extract of KRG (KRGE) was applied to GnRH neurons to identify the receptors activated by KRGE. The brain slice patch clamp technique in whole cell and perforated patch was used to clarify the effect of KRGE on the membrane currents and membrane potentials of GnRH neurons. Application of KRGE (3 ${\mu}g$/${\mu}L$) under whole cell patch induced remarkable inward currents (56.17${\pm}$7.45 pA, n=25) and depolarization (12.91${\pm}$3.80 mV, n=4) in GnRH neurons under high $Cl^-$ pipette solution condition. These inward currents were not only reproducible, but also concentration dependent. In addition, inward currents and depolarization induced by KRGE persisted in the presence of the voltage gated $Na^+$ channel blocker tetrodotoxin (TTX), suggesting that the responses by KRGE were postsynaptic events. Application of KRGE under the gramicidin perforated patch induced depolarization in the presence of TTX suggesting its physiological significance on GnRH response. Further, the KRGE-induced inward currents were partially blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; non-NMDA glutamate receptor antagonist, 10 ${\mu}M$) or picrotoxin (PIC; $GABA_A$ receptor antagonist, 50 ${\mu}M$), and almost blocked by PIC and CNQX mixture. Taken together, these results suggest that KRGE contains ingredients with possible GABA and non-NMDA glutamate receptor mimetic activity, and may play an important role in the endocrine function of reproductive physiology, via activation of $GABA_A$ and non-NMDA glutamate receptors in GnRH neurons.

• The Korean Journal of Physiology and Pharmacology
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• 제14권3호
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• pp.151-156
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• 2010

This study was performed to investigate the role of glutamate neurotransmitter system on gastrointestinal motility in a middle cerebral artery occlusion (MCAO) model of rats. The right middle cerebral artery was occluded by surgical operation, and intestinal transit and geometric center as a parameter of gastrointestinal motility and expression of c-Fos protein in the insular cortex and cingulate cortex were measured at 2 and 12 h after MCAO. Intestinal transit was $66.3{\pm}7.5%$ and $62.3{\pm}5.7%$ 2 and 12 h after sham operation, respectively, and MCAO significantly decreased intestinal transit to $39.0{\pm}3.5%$ and $47.0{\pm}5.1%$ at 2 and 12 h after the occlusion, respectively (p<0.01). The geometric center was $5.6{\pm}0.4$ and $5.2{\pm}0.9$ at 2 and 12 h after sham operation, respectively, and MCAO significantly decreased geometric center to $2.9{\pm}0.8$ and $3.0{\pm}0.3$ at 2 and 12 h after the occlusion, respectively (p<0.01). In control animals, injection of atropine decreased intestinal transit to $35.9{\pm}5.2%$, and injection of glutamate NMDA receptor antagonist, MK-801, decreased intestinal transit to $28.8{\pm}9.5%$. Pretreatment with MK-801, a glutamate NMDA receptor antagonist, in the MCAO group decreased intestinal transit to $11.8{\pm}3.2%$, which was significantly decreased compared to MCAO group (p<0.01). MCAO markedly increased the expression of c-Fos protein in the insular cortex and cingulate cortex ipsilateral to the occlusion 2 h after MCAO, and pretreatment with MK-801 produced marked reduction of c-Fos protein expression compared to MCAO group (p<0.01). These results suggest that modulation of gastrointestinal motility after MCAO might be partially mediated through a glutamate NMDA receptor system.

• The Korean Journal of Physiology and Pharmacology
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• 제26권6호
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• pp.531-540
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• 2022

Group 1 metabotropic glutamate receptors (mGluRs) can positively affect postsynaptic neuronal excitability and epileptogenesis. The objective of the present study was to determine whether group 1 mGluRs might be involved in synaptically-induced intracellular free Ca²⁺ concentration ([Ca²⁺]_i) spikes and neuronal cell death induced by 0.1 mM Mg²⁺ and 10 µM glycine in cultured rat hippocampal neurons from embryonic day 17 fetal Sprague-Dawley rats using imaging methods for Ca²⁺ and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays for cell survival. Reduction of extracellular Mg²⁺ concentration ([Mg²⁺]_o) to 0.1 mM induced repetitive [Ca²⁺]_i spikes within 30 sec at day 11.5. The mGluR5 antagonist 6-Methyl2-(phenylethynyl) pyridine (MPEP) almost completely inhibited the [Ca²⁺]_i spikes, but the mGluR1 antagonist LY367385 did not. The group 1 mGluRs agonist, 3,5-dihydroxyphenylglycine (DHPG), significantly increased the [Ca²⁺]_i spikes. The phospholipase C inhibitor U73122 significantly inhibited the [Ca²⁺]_i spikes in the absence or presence of DHPG. The IP₃ receptor antagonist 2-aminoethoxydiphenyl borate or the ryanodine receptor antagonist 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate also significantly inhibited the [Ca²⁺]_i spikes in the absence or presence of DHPG. The TRPC channel inhibitors SKF96365 and flufenamic acid significantly inhibited the [Ca²⁺]_i spikes in the absence or presence of DHPG. The mGluR5 antagonist MPEP significantly increased the neuronal cell survival, but mGluR1 antagonist LY367385 did not. These results suggest a possibility that mGluR5 is involved in synaptically-induced [Ca²⁺]_i spikes and neuronal cell death in cultured rat hippocampal neurons by releasing Ca²⁺ from IP₃ and ryanodine-sensitive intracellular stores and activating TRPC channels.

• The Korean Journal of Physiology and Pharmacology
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• 제13권3호
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• pp.209-214
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• 2009

The striatum receives glutamatergic afferents from the cortex and thalamus, and these synaptic transmissions are mediated by ${\alpha}$-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl D-aspartate (NMDA) receptors. The purpose of this study was to characterize glutamate receptors by analyzing NMDA/AMPA ratio and rectification of AMPA and NMDA excitatory postsynaptic currents (EPSCs) using a whole-cell voltage-clamp method in the dorsal striatum. Receptor antagonists were used to isolate receptor or subunit specific EPSC, such as (DL)-2-amino-5-phosphonovaleric acid (APV), an NMDA receptor antagonist, ifenprodil, an NR2B antagonist, CNQX, an AMPA receptor antagonist and IEM-1460, a GluR2-lacking AMPA receptor blocker. AMPA and NMDA EPSCs were recorded at - 70 and + 40 mV, respectively. Rectification index was calculated by current ratio of EPSCs between + 50 and - 50 mV. NMDA/AMPA ratio was 0.20${\pm}$0.05, AMPA receptor ratio of GluR2-lacking/GluR2-containing subunit was 0.26${\pm}$0.05 and NMDA receptor ratio of NR2B/NR2A subunit was 0.32${\pm}$0.03. The rectification index (control 2.39${\pm}$0.27) was decreased in the presence of both APV and combination of APV and IEM-1460 (1.02${\pm}$0.11 and 0.93${\pm}$0.09, respectively). These results suggest that the major components of the striatal glutamate receptors are GluR2-containing AMPA receptors and NR2A-containing NMDA receptors. Our results may provide useful information for corticostriatal synaptic transmission and plasticity studies.

• Journal of Ginseng Research
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• 제35권2호
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• pp.219-225
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• 2011

Korean red ginseng (KRG) is a valuable and important traditional medicine in East Asian countries and is currently used extensively for botanical products in the world. KRG has both stimulatory and inhibitory effects on the central nervous system (CNS) suggesting its complicated action mechanisms. The substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis (Vc) are involved in orofacial nociceptive processing. Some studies reported that KRG has antinociceptive effects, but there are few reports of the functional studies of KRG on the SG neurons of the Vc. In this study, a whole cell patch clamp study was performed to examine the action mechanism of a KRG extract on the SG neurons of the Vc from juvenile mice. KRG induced short-lived and repeatable inward currents on all the SG neurons tested in the high chloride pipette solution. The KRG-induced inward currents were concentration dependent and were maintained in the presence of tetrodotoxin, a voltage gated $Na^+$ channel blocker. The KRG-induced inward currents were suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione, a non-N-methyl-D-aspartate (NMDA) glutamate receptor antagonist and/or picrotoxin, a gamma-aminobutyric acid $(GABA)_A$ receptor antagonist. However, the inward currents were not suppressed by d,l-2-amino-5-phosphonopentanoic acid, an NMDA receptor antagonist. These results show that KRG has excitatory effects on the SG neurons of the Vc via the activation of non-NMDA glutamate receptor as well as an inhibitory effect by activation of the $GABA_A$ receptor, indicating the KRG has both stimulatory and inhibitory effects on the CNS. In addition, KRG may be a potential target for modulating orofacial pain processing.

• Archives of Pharmacal Research
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• 제24권6호
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• pp.613-617
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• 2001

The present study examined the hypothesis that NMDA, AMPA/Kainate, and metabotropic (mGlu) glutamate receptors contribute to a behavioral stimulation induced by activation of dopamine receptors by comparing responses in apomorphine-induced cage climbing behaviors in mice. MK-801, CNQX, and MCPG were served as the NMDA receptor, AMPA/Kainate receptor, and mGlu receptor antagonist, respectively, to elucidate the glutamatergic modulation in apomorphine-induced eopaminergic activation in mice. Drugs were administered intracerebroventricularly (i.c.v.) into the mouse brain 15 min before the apomorphine treatment (2 mg/kg, s.c.). 1.c.v. injection of MK-801 inhibited the apomorphine-induced cage climbing behavior dose-dependently. However, treatments with CNQX and MCPG did not any significant change in apomorphine-induced cage climbing behavior in mice. These results suggest that stimulation of NMDA type of glutamate receptors could contribute to the dopaminergic sti mutation, but not AMPA/Kainate and mGlu type glutamate receptors.