• Biomolecules & Therapeutics
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• v.5 no.1
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• pp.94-99
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• 1997

Capsaicin is known to be an analgesic agent, affecting the synthesis, storage, , transport and release of substance p, the principal neurotransmitter of pain from periphery to the central nervous system(CNS). DA-5018, a newly synthesized capsaicin derivative has shown potent analgesic effect comparable to that of morphine in various rat models of experimentally inducted acute pairs. In this study the mechanism of analgesic actlvity of DA-5018 was examined. First, the electrically-evoked contraction of guinea pig trachea was inhibited by DA-5018 and these inhibition was recovered by incubation with capsafepine(3$\muM$), capsaicin receptor antagonist and this result suggested that DA-5018 has affinity on capsaicin receptor. The correlation between the norciceptive threshold and the release of substance P was evaluated. In vivo perfusion of slices of the rat spinal cord with DA-5018(10, 100$\muM$) produced a significant increase of the release of substance P and this increase was less than that of capsaicin(10$\muM$). The norciceptive threshold of rat treated with DA-5018(1 mg/kg, p.o) in tall pinch test increased from 2.9$\pm$0.3 to 23.5 $\pm$6.61. Tail pinch latency increased to a maximun at 15 min after DA-5018 treatment and then declined to control values by 120 min. The capsaicin-evoked release ot substance P from the spinal cord slices of rat treated with DA-5018 reduced from 2.38$\pm$ 0.79 to 0.69$\pm$ 0.26 pg/mg wet weight. This reduction reached to a minium at 15 min after DA-5018 treatment and then recovered to control value by 120 min. These results mean that analgesic activity of DA-5018 is due to release of substance P The effect of DA-5018 cream on electrically-evoked neurogenic inflammation of rat saphenous nerve was compared with capsaicin (zostrix-HP). DA-5018 showed 34% inhibition of the neurogenic extravasation while capsaicin showed significant 67% inhibition. This result indicates that the potency of DA-5018 in the release of substance P is less than that of capsaicin. These results suggest that the release of substance P is partially involved in the mechanism of analgesic action of DA-50l8.

• Journal of Oriental Neuropsychiatry
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• v.16 no.2
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• pp.13-24
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• 2005

Background and Objectives : Acupuncture as a therapeutic intervention is widely used for the treatment of many functional disorders such as substance abuse and mental dysfunction. Clinical trials are currently underway to determine the effectiveness of acupuncture in the treatment of drug addiction. Yet, there are still many unanswered questions about the basic mechanism of acupuncture. Studies have shown that both the psychomotor stimulant effects and rewarding properties of addictive drugs, including morphine, are sensitized by repeated drug administration and raised the possibility that both of these effects may be linked to the same or closely overlapping the mesolimbic dopamine systems. Neiguan (PC6) point on the pericardium channel which is associated with the brain and its mental function, has been used to treat mental, psychosomatic disorders and gastroenterological disorders. The present study was designed to investigate the effect of acupuncture on repeated morphine-induced changes in extracellular dopamine levels using in vivo microdialysis and to measure the effect of acupuncture on Fos-like immunoreactivity. Methods : Male Sprague-Dawley rats were treated twice a day for three days with increasing doses of morphine (10, 20 and 40 mg/kg, s.c.) or with saline. After 15 days of withdrawal, rats were challenged with morphine hydrochloride (5 mg/kg, s.c.). Acupuncture was applied at bilateral Neiguan (PC6) points for 1 min after the morphine challenge. Results showed that acupuncture at the specific acupoint PC6, but not at control points (tail and HE8) significantly decreased Fos-like immunoreactivity induced by a systemic morphine challenge or a single s.c. morphine injection in the morphine-repeated animals. Results and Conclusions : These results suggest that reduction in sensitization may be one mechanism whereby acupuncture alleviates morphine craving in addicts. Moreover, in a more general sense these results suggest that acupuncture can be used as a therapeutic intervention for correcting reversible malfunction of the body by direction of brain pathway and thus acupuncture can contribute to the biochemical balance in the central nervous system by regulating neurotransmitters.

• The Korean Journal of Zoology
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• v.33 no.4
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• pp.461-467
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• 1990

To investigate the neurological effect of acrylamide, whole brain of Intoxicated mouse induced early hindlimbs ataxia was examined by using the methods of SDS-PAGE and two-dimensional electrophoresis. In the gel patterns by SDS-PAGE, when the patterns of each group were compared relatively, there were no remakable changes but in the patterns of 2D-PAGE, some protein alterations were observed. Especially, the spots containing 20 (14,500, 5.64) and 21 (19,900, 6.78) were disappeared, and the spots 9 (31,300, 5.82), 11 (31,300, 5.36) and 19 (16,400, 5.42) showed marked decrease relatively in the case of treatment group. Among these changed spots, the spot 20 (14,500, 5.64) showed higher quantity than that of control group but several spots containing the spots 11 (31,300, 5.36), and 19(16.400, 5.42) were identical or equal to those of control In quantity in the case of recovery group. It seems that acrylamide might already inhibit the brain protein synthesis mechanism at the time of onset of distal neuropathy by participation in the protein metabolism so as to impair the brain regulation ability followed by a malfunction of mouse central nervous system (CNS) and recovery is gradually progressed with the dose and duration dependence after the cessation of acrylamide administration.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.246-246
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• 1996

The glucuronide conjugates of morphine have been claimed to exert significant neuropharmacological effects. Morphine-6-glucuronide (M6G) may be a potent opioid agonist in vivo, and morphine-3-glucuronide (M3G) may act as a weak opioid antagonist. The present study addressed the permeability of the blood-brain barrier (BBB) for these metabolites compared to morphine. Tracers were prepared by enzymatic glucuronidation of U-methyl-$^3$H]-morphine. Brain uptake in rats was measured by the internal carotid artery perfusion technique and after i.v. bolus injections. In the perfusion experiments morphine showed a permeability-surface area product (PS) of 3.52${\pm}$0.61 ${\mu}$L min$\^$-1/ g$\^$-1/ Uptake seems to be mediated by passive diffusion and was not saturable by 100 ${\mu}$M morphine in the perfusate. The BBB permeability of [$^3$H]-M3G and [$^3$H]-M6G was too low to be quantified after 5 min of perfusion. Brain uptake of [$^3$H]-M3G and [$^3$H]-M6G 60 min after i.v. bolus injection reached 0.0060${\pm}$0.0003 and 0.0030${\pm}$0.0005% injected dose per g, respectively. From these brain concentrations and from the corresponding plasma concentration - time curves, BBB PS values of 0.14${\pm}$ 0.02 ${\mu}$L min$\^$-1/g$\^$-1/ and 0.11 ${\pm}$ 0.01 ${\mu}$L min$\^$-1/g$\^$-1/, respectively, were calculated. The ratio of BBB PS values is complementary to the analgesic potencies of morphine and M6G after different routes of administration. The low PS of MSG explains, why it is approximate]y equipotent to morphine after systemic injection, although it is about 2 orders of magnitude more potent than morphine after administration directly into the central nervous system.

• Journal of Korean Neurosurgical Society
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• v.30 no.4
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• pp.417-424
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• 2001

Objective : Adrenal medullary chromaffin cells are known to release analgesic substances such as opioides and catecholamines. Transplantation of them is a novel method that challenges current approaches in treating chronic pain. The transplantation of xenogeneic chromaffin cells into the central nervous system(CNS) supply antinociception in animals. In this study, we investigated the analgesic effects of rat adrenal medullary chromaffin cells transplanted into the CNS of the mouse. To study the antinociceptive efficacy of transplanted chromaffin cells, the survival of rat adrenal medullary chromaffin cells transplanted into the CNS of mouse was determined. Methods : The adrenal medullary chromaffin cells isolated from rat were transplanted into the striatum of mouse. These cells were confirmed of the release of Met-enkephalin and Leu-enkephalin by HPLC, and immunoblots for tyrosine hydroxylase(TH). Two weeks after transplantation, we performed immunohistochemistry for TH to determine the survival of implanted cells and assessed pain sensitivity at the same time. Results : The isolated rat adrenal medullary chromaffin cells were positive for anti-TH antibody and released Met-enkephalin and Leu-enkephalin more than rat endothelial cells. Transplanted rat chromaffin cells were stained with anti-TH antibody in striatum of mouse after 2 weeks. Pain sensitivity was reduced on the chromaffin cell-transplanted mouse compared to endothelial cell-transplanted mouse by the hot plate test. Conclusion : These results suggest that the rat chromaffin cells were suitably transplanted into the CNS of mouse. This approach could be used as a therapy for reducing of chronic pain induced by cancer or neuronal injury.

• BMB Reports
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• v.39 no.4
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• pp.339-345
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• 2006

The blood-neural barrier (BNB), including blood-brain barrier (BBB) and blood-retinal barrier (BRB), is an endothelial barrier constructed by an extensive network of endothelial cells, astrocytes and neurons to form functional 'neurovascular units', which has an important role in maintaining a precisely regulated microenvironment for reliable neuronal activity. Although failure of the BNB may be a precipitating event or a consequence, the breakdown of BNB is closely related with the development and progression of CNS diseases. Therefore, BNB is most essential in the regulation of microenvironment of the CNS. The BNB is a selective diffusion barrier characterized by tight junctions between endothelial cells, lack of fenestrations, and specific BNB transporters. The BNB have been shown to be astrocyte dependent, for it is formed by the CNS capillary endothelial cells, surrounded by astrocytic end-foot processes. Given the anatomical associations with endothelial cells, it could be supposed that astrocytes play a role in the development, maintenance, and breakdown of the BNB. Therefore, astrocytes-endothelial cells interaction influences the BNB in both physiological and pathological conditions. If we better understand mutual interactions between astrocytes and endothelial cells, in the near future, we could provide a critical solution to the BNB problems and create new opportunities for future success of treating CNS diseases. Here, we focused astrocyte-endothelial cell interaction in the formation and function of the BNB.

• Journal of Oriental Neuropsychiatry
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• v.27 no.3
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• pp.169-184
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• 2016

Objectives: To investigate the neurophysiological effect of acupuncture treatment on insomnia patients using quantitative electroencephalography (QEEG) and standardized Low Resolution Brain Electromagnetic Tomography method (sLORETA).Background: Insomnia is one of the commonly encountered symptoms in primary medical care. Recent studies of acupuncture for insomnia reported that the acupuncture groups showed significant improvements compared with the control groups. However, the neurophysiological mechanism of acupuncture in the treatment of insomnia has not been revealed and a few studies have measured the effect of acupuncture treatment using QEEG.Methods: Participants who had some problems in initiating or maintaining sleep, or had non-restorative sleep for more than 3 days a week and ISI scores above 8 and below 21 were treated by acupuncture for 2 weeks (3 times a week, total 6 times). We assessed the effectiveness of acupuncture for insomnia by the PSQI (Pittsburgh Sleep Quality Index) at baseline and at 2 weeks after the end of treatment (4th week). Also, we performed EEG and analysed the EEG data at baseline and at the end of treatment (2nd week) on the linked ears montage using the Neuroguide software program and sLORETA.Results: Thirty-two participants were enrolled and 2 participants dropped out because of personal reasons. Among the 30 participants, EEGs of 12 participants were included in the analysis of QEEG and sLORETA. Total score on the ISI and PSQI was significantly decreased after acupuncture treatment. The number of electrodes exceeding the range of 90% (±1.65) or 95% (±1.96) in the z scored absolute power of beta was significantly decreased after acupuncture treatment. There was no significant change in brain activation between pre- and post-acupuncture using sLORETA.Conclusions: The deviation of absolute power compared to the normative database was significantly decreased after acupuncture treatment in the alpha and beta ranges. Therefore, we suggest that acupuncture treatment for insomnia might be effective through the central nervous system especially in the brain. There are many limitations to drawing any conclusion. Further studies are needed in the future to overcome these limitations.

• The Korean Journal of Physiology and Pharmacology
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• v.15 no.1
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• pp.61-66
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• 2011

P2Y receptors are metabotropic G-protein-coupled receptors, which are involved in many important biologic functions in the central nervous system including retina. Subtypes of P2Y receptors in retinal tissue vary according to the species and the cell types. We examined the molecular and pharmacologic profiles of P2Y purinoceptors in retinoblastoma cell, which has not been identified yet. To achieve this goal, we used $Ca^{2+}$ imaging technique and western blot analysis in WERI-Rb-1 cell, a human retinoblastoma cell line. ATP ($10\;{\mu}M$) elicited strong but transient $[Ca^{2+}]_i$ increase in a concentration dependent manner from more than 80% of the WERI-Rb-1 cells (n=46). Orders of potency of P2Y agonists in evoking $[Ca^{2+}]_i$ transients were 2MeS-ATP>ATP>>UTP=${\alpha}{\beta}$-MeATP, which was compatible with the subclass of $P2Y_1$ receptor. The $[Ca^{2+}]_i$ transients evoked by applications of 2MeS-ATP and/or ATP were also profoundly suppressed in the presence of $P2Y_1$ selective blocker (MRS 2179; $30\;{\mu}M$). $P2Y_1$ receptor expression in WERI-Rb-1 cells was also identified by using western blot. Taken together, $P2Y_1$ receptor is mainly expressed in a retinoblastoma cell, which elicits $Ca^{2+}$ release from internal $Ca^{2+}$ storage sites via the phospholipase C-mediated pathway. $P2Y_1$ receptor activation in retinoblastoma cell could be a useful model to investigate the role of purinergic $[Ca^{2+}]_i$ signaling in neural tissue as well as to find a novel therapeutic target to this lethal cancer.

• Journal of Pharmaceutical Investigation
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• v.32 no.2
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• pp.127-133
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• 2002

Levosulpiride is the 1evo-enantiomer form of racemic sulpiride, a benzamide derivative selectively inhibiting dopaminergic $D_2$ receptors at the trigger zone both in the central nervous system and in the gastrointestinal tract. The purpose of the present study was to evaluate the bioequiva1ence of two levosulpiride tablets, Levopride (SK Pharmaceutical Co., Ltd.) and Levopid (Dae Won Pharmaceutical Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). The levosulpiride release from the two levosulpiride tablets in vitro was tested using KP VII Apparatus II method with various different kinds of dissolution media (pH 1.2, 4.0, 6.8 buffer solution and water). Twenty eight normal male volunteers, $23.82{\pm}3.26$ years in age and $69.13{\pm}8.58$ kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one tablet containing 25 mg of levosulpiride was orally administered, blood was taken at predetermined time intervals and the concentrations of levosulpiride in serum were determined using HPLC method with fluorescence detector. The dissolution profiles of two levosulpiride tablets were very similar at all dissolution media. Besides, the pharmacokinetic parameters such as $AUC_t,\;C_{max}\;and\;T_{max}$ were calculated and ANOVA test was utilized for the statistical analysis of the parameters using logarithmically transformed $AUC_t\;and\;C_{max}$ and untransformed $T_{max}$. The results showed that the differences in $AUC_t,\;C_{max}\;and\;T_{max}$ between two tablets based on the Levopride were -1.17%, 1.20% and -1.09%, respectively. There were no sequence effects between two tablets in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log(0.8) to log(1.25) $(e.g.,\;log(0.93){\sim}log(1.07)\;and\;log(0.90){\sim}log(1.14)\;for\;AUC_t\;and\;C_{max}$, respectively). The 90% confidence interval using untransformed data was within ${\pm}20%$ $(e.g.,\;-19.47{\sim}16.20\;for\;T_{max})$. All parameters met the criteria of KFDA guideline for bioequivalence, indicating that Levopid tablet is bioequivalent to Levopride tablet.

• The Korean Journal of Pharmacology
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• v.24 no.1
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• pp.17-29
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• 1988

The author examined the effects of lidocaine on the veratrine-or potassium-induced release of neurotransmitters to determine the possible role of amino acid neurotransmitters in lidocaine-induced convulsion. The examined transmitters were gamma-aminobutyric acid (GABA), aspartic acid, glutamic acid and norepinephrine which are released from the synaptosomes. Furthermore, the effects of lidocaine on the binding to receptors and synaptosomal uptake of the two transmitters, GABA and glutamic acid, were determined in crude synaptic membranes and synaptosomes. In addition, the effects of propranolol, norepinephrine and serotonin on the release of amino acid neurotransmitters were also examined. The veratrine-induced release of GABA was most severely inhibited by lidocaine and propranolol, while norepinephrine and serotonin reduced the release of aspartic acid and glutamic acid more than the GABA release. Generally the potassium-induced release was much more resistant to the lidocaine action than the veratrine-induced release. Among the neurotransmitters examined, the aspartic acid release was most prone to the lidocaine action, while the GABA release was most resistant. Concentrations of lidocaine below 1 mM did not significantly change the GABA and glutamic acid receptor binding and uptake. These results indicate that the blocking of sodium channels by lidocaine can result in the selective depression of the GABA release. This may result in unlimited excitation of the central nervous system.