• The Korean Journal of Pain
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• v.34 no.1
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• pp.58-65
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• 2021

Background: Supraspinal delivery of neurotensin (NTS), which may contribute to the effect of a systemically administered agonist, has been reported to be either pronociceptive or antinociceptive. Here, we evaluated the effects of systemically administered NTSR1 agonist in a rat model of neuropathic pain and elucidated the underlying supraspinal mechanism. Methods: Neuropathic pain was induced by L5 and L6 spinal nerve ligation in male Sprague-Dawley rats. The effects of intraperitoneally administered NTSR1 agonist PD 149163 was assessed using von Frey filaments. To examine the role of 5-HT neurotransmission, a serotonin (5-HT) receptor antagonist dihydroergocristine was pretreated intrathecally, and spinal microdialysis studies were performed to measure the change in extracellular level of 5-HT in response to PD 149163 administration. To investigate the supraspinal mechanism, NTSR1 antagonist 48692 was microinjected into the rostral ventromedial medulla (RVM) prior to systemic PD 149163. Additionally, the effect of intrathecal DHE on intra-RVM PD 149163 was assessed. Results: Intraperitoneally administered PD 149163 exhibited a dose-dependent attenuation of mechanical allodynia. This effect was partially reversed by intrathecal pretreatment with dihydroergocristine and was accompanied by an increased extracellular level of 5-HT in the spinal cord. The PD 149163-produced antinociception was also blocked by intra-RVM SB 48692. Direct injection of PD 149163 into the RVM mimicked the maximum effect of the same drug delivered intraperitoneally, which was reversed by intrathecal dihydroergocristine. Conclusions: These observations indicate that systemically administered NTSR1 agonist produces antinociception through the NTSR1 in the RVM, activating descending serotonergic projection to release 5-HT into the spinal dorsal horn.

• BMB Reports
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• v.46 no.6
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• pp.295-304
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• 2013

Extracellular acidification occurs not only in pathological conditions such as inflammation and brain ischemia, but also in normal physiological conditions such as synaptic transmission. Acid-sensing ion channels (ASICs) can detect a broad range of physiological pH changes during pathological and synaptic cellular activities. ASICs are voltage-independent, proton-gated cation channels widely expressed throughout the central and peripheral nervous system. Activation of ASICs is involved in pain perception, synaptic plasticity, learning and memory, fear, ischemic neuronal injury, seizure termination, neuronal degeneration, and mechanosensation. Therefore, ASICs emerge as potential therapeutic targets for manipulating pain and neurological diseases. The activity of these channels can be regulated by many factors such as lactate, $Zn^{2+}$, and Phe-Met-Arg-Phe amide (FMRFamide)-like neuropeptides by interacting with the channel's large extracellular loop. ASICs are also modulated by G protein-coupled receptors such as CB1 cannabinoid receptors and 5-$HT_2$. This review focuses on the physiological roles of ASICs and the molecular mechanisms by which these channels are regulated.

• Journal of Ginseng Research
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• v.29 no.1
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• pp.19-26
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• 2005

The last two decades have shown a marked expansion in publications of diverse effects of Panax ginseng. Ginsenosides, as active ingredients of Panax ginseng, are saponins found in only ginseng. Recently, a line of evidences shows that ginsenosides regulate various types of ion channel activity such as $Ca^{2+},\;K^+,\;Na^+,\;Cl^-$, or ligand gated ion channels (i.e. $5-HT_3$, nicotinic acetylcholine, or NMDA receptor) in neuronal, non-neuronal cells, and heterologously expressed cells. Ginsenosides inhibit voltage-dependent $Ca^{2+},\;K^+,\;and\;Na^+$ channels, whereas ginsenosides activate $Ca^{2+}-activated\;Cl^-\;and\;Ca^{2+}-activated\;K^+$ channels. Ginsenosides also inhibit excitatory ligand-gated ion channels such as $5-HT_3$, nicotinic acetylcholine, and NMDA receptors. This review will introduce recent findings on the ginsenoside-induced differential regulations of ion channel activities and will further expand the possibilities how these ginsenoside-induced ion channel regulations are coupled to biological effects of Panax ginseng.

• CELLMED
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• v.2 no.4
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• pp.38.1-38.6
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• 2012

The present study aimed to determine the possible mechanisms of the peripheral antinociception of the aqueous extracts of Dicranopteris linearis (AEDL), Melastoma malabathricum (AEMM) and Bauhinia purpurea (AEBP) leaves in mice. Briefly, the antinociceptive profile of each extract (300, 500, and 1000 mg/kg; subcutaneous (s.c.)), was established using the abdominal constriction test. A single dose (500 mg/kg) of each extract (s.c.) was pre-challenged for 10 min with various pain receptors' antagonists or pain mediators' blockers and 30 min later subjected to the antinociceptive assay to determine the possible mechanism(s) involved. Based on the results obtained, all extracts exerted significant (p < 0.05) antinociceptive activity with dose-dependent activity observed only with the AEMM. Furthermore, the antinociception of AEDL was attenuated by naloxone, atropine, yohimbine and theophylline; AEMM was reversed by yohimbine, theophylline, thioperamide, pindolol, reserpine, and 4-chloro-DL-phenylalanine methyl ester hydrochloride; and of AEBP was inhibited by naloxone, haloperidol, yohimbine and reserpine. In conclusion, the antinociceptive activity of those extracts possibly involved the activation of several pain receptors (i.e. opioids, muscarinic, ${\alpha}_2$-adrenergic and adenosine receptors, adenosine, H3-histaminergic and $5HT_{1A}$, dopaminergic receptors).

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.6
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• pp.677-685
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• 1998

To investigate the effects of neonatal stress on behavior and neurochemistry, rats were exposed to the footshock stress on postnatal day (PND) 14 or PNDs 14 and 21. Rats were exposed to uncontrollable electric shocks delivered to the floor with a constant current (0.8 mA) for 5 sec period. Daily sessions consisted of 60 trials on a random time schedule with an average of 55 sec. The first exposure to footshocks on PND 14 decreased body weight gain for 1 day. However, the second exposure to footshocks on PND 21 did not affect body weight gain. Exploratory activity was measured by exposing a rat to a novel environment 24 h after experience of footshocks. Similar to the body weight changes, a decreased activity was noted after the first exposure to footshocks, while no changed activity was noted after the second exposure to footshocks. However, the Bmax value of $5-HT_{2A/2C}$ receptors in the cortex decreased by the second exposure to footshocks, but not by the first exposure to footshocks. Moreover, an autoradiographic study revealed that the density of $[^3H]dexamethasone$ binding in hippocampus decreased in rats exposed to footshocks 4 times during PND $14{\sim}20.$ These results suggest that the uncontrollable footshock stress changes 5-hydroxytryptamine and glucocorticoid receptor systems acutely and that the repeated exposure to the same stress may not elicit behavioral alterations by the compensatory activity of young brain although changes in some neurochemistry exist.

• Bulletin of the Korean Chemical Society
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• v.26 no.11
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• pp.1701-1705
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• 2005

We have established an efficient method for the synthesis of the arylpiperazine derivatives in which the acylation of 2-aminopyridine, the coupling reaction of the acyl compound with piperazines, and reduction of the arylpiperazines were performed under a microwave irradiation (300 W) to afford the corresponding target compounds in quantitative yields. In all cases, the reaction times were remarkably reduced when compared with those of the conventional method.

• Sleep Medicine and Psychophysiology
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• v.20 no.1
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• pp.5-9
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• 2013

One of hypothesis is that sleep loss related to a decrease in serotonergic activity plays a significant role in attempted suicide. A growing evidence suggests that central serotonergic activity plays a key role in the etiology of suicide. It has been reported that the cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, were reduced in suicide attempters. In addition, there is evidence that tryptophan hydroxylase is associated with suicide. The association between sleep and suicide was also suggested by some researchers. Several recent studies have showed the association between sleep disturbance and suicide rates in patients with mental disorders and in a general population. In addition, it has been suggested that serotonin plays a role in maintaining arousal and regulating muscle tone and in regulating some of the phasic events of REM sleep. Especially, it is well-known that 5-HT2 receptors are related to slow wave sleep. In conclusion, it is clear that sleep, serotonin activity, and suicide are linked, although the direction of causation needs clarification. In future, large population-based cohort studies are needed to demonstrate the direction of causation in the relationships between sleep, serotonin activity, and suicide.

• The Korean Journal of Pharmacology
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• v.29 no.2
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• pp.189-193
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• 1993

Exposure of dissociated cultures from fetal rat brainstem to glutamate for upto 6 h decreased cellular contents of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in a concentration- and time-dependent manner. In addition, glutamate induced lactate dehydrogenase leakage. Tetrodotoxin did not block the effects induced by glutamate. MK-801 $(1{\mu}M)$, an N-methyl-D-aspartate (NMDA) channel blocker, but not 6-cyano-2,3-dihydroxy-7-nitro-quinoxazoline $(CNQX;\;3{\mu}M)$, a non-NMDA receptor antagonist, blocked glutamate-induced effects, indicating that these glutamate-induced responses are mediated through NMDA receptors.

• Korean Journal of Biological Psychiatry
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• v.8 no.2
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• pp.208-219
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• 2001

The pharmacotherapy of schizophrenia exhibits wide inter-individual variabilities in clinical efficacy and adverse effects. Recently, human genetic diversity has been known as one of the essential factors to the variation in human drug response. This suggests that drug therapy should be tailored to the genetic characteristics of the individual. Pharmacogenetics is the field of investigation that attempts to elucidate genetic basis of an individual's responses to pharmacotherapy, considering drug effects divided into two categories as pharmacokinetics and pharmacodynamics. The emerging field of pharmacogenomics, which focuses on genetic determinants of drug response at the level of the entire human genome, is important for development and prescription of safer and more effective individually tailored drugs and will aid in understanding how genetics influence drug response. In schizophrenia, pharmacogenetic studies have shown the role of genetic variants of the cytochrome P450 enzymes such as CYP2D6, CYP2C19, and CYP2A1 in the metabolism of antipsychotic drugs. At the level of drug targets, variants of the dopamine $D_2$, $D_3$ and $D_4$, and 5-$HT_{2A}$ and 5-$HT_{2C}$ receptors have been examined. The pharmacogenetic studies in schizophrenia presently shows controversial findings which may be related to the multiple involvement of genes with relatively small effects and to the lack of standardized phenotypes. For further development in the pharmacogenomics of schizophrenia, there would be required the extensive outcome measures and definitions, and the powerful new tools of genomics, proteomics and so on.

• Biomolecules & Therapeutics
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• v.28 no.1
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• pp.83-91
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• 2020

Tryptamines are monoamine alkaloids with hallucinogenic properties and are widely abused worldwide. To hasten the regulations of novel substances and predict their abuse potential, we designed and synthesized four novel synthetic tryptamine analogs: Pyrrolidino tryptamine hydrochloride (PYT HCl), Piperidino tryptamine hydrochloride (PIT HCl), N,N-dibutyl tryptamine hydrochloride (DBT HCl), and 2-Methyl tryptamine hydrochloride (2-MT HCl). Then, we evaluated their rewarding and reinforcing effects using the conditioned place preference (CPP) and self-administration (SA) paradigms. We conducted an open field test (OFT) to determine the effects of the novel compounds on locomotor activity. A head-twitch response (HTR) was also performed to characterize their hallucinogenic properties. Lastly, we examined the effects of the compounds on 5-HTR1a and 5-HTR2a in the prefrontal cortex using a quantitative real-time polymerase chain reaction (qRT-PCR) assay. None of the compounds induced CPP in mice or initiated SA in rats. PYT HCl and PIT HCl reduced the locomotor activity and elevated the 5-HTR1a mRNA levels in mice. Acute and repeated treatment with the novel tryptamines elicited HTR in mice. Furthermore, a drug challenge involving a 7-day abstinence from drug use produced higher HTR than acute and repeated treatments. Both the acute treatment and drug challenge increased the 5-HTR2a mRNA levels. Ketanserin blocked the induced HTR. Taken together, the findings suggest that PYT HCl, PIT HCl, DBT HCl, and 2-MT HCl produce hallucinogenic effects via 5-HTR2a stimulation, but may have low abuse potential.