• Proceedings of the Ginseng society Conference
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• 1990.06a
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• pp.36-44
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• 1990

The analgesic effect of morphine was antagonized and the development of tolerance was suppressed by the modification of the neurologic function in the animals treated with ginseng saponins. The activation of the spinal descending inhibitory systems as well as the supraspinal structures by the administration of morphine was inhibited in the animals treated with ginseng saponins intracerebrally or intrathecally The development of morphine tolerance and dependence, and the abrupt expression of naloxone induced abstinence syndrome were also inhibited by ginsenoside Kbl , Rba, Rgl and Re. These results suggest that ginsenoside Kbl, Rba, Rgl and Re are the bioactive components of panax ginseng on the inhibition of the development of morphine tolerance and dependence, and the inhibition of abrupt abstinence syndrome. In addition, further research on the minor components of Panax ginseng should be investigated. A single or daily treatment with ginseng saponins did not induce any appreciable changes in the brain level of monoamines at the various time intervals and at the various day intervals, respectively The inhibitory or facilitated effects of ginseng saponins on electrically evoked contractions in guinea pig ileum (U-receptor) and mouse was definers (5·receptor) were not mediated through opioid receptors. The antagonism of a x receptor agonist, U-, iO.488H was also not mediated through opioid receptors in the animals treated with ginseng saponins, bolt mediated through serotonergic mechanisms. Ginseng saponins inhibited morphine S-dehydrogenase that catalyzed the production of morphine from morphine, and increased hepatic glutathione contents for the detoxification of morphine. This result suggests that the dual action of the above plays an important role in the inhibition of the development of morphine tolerance and dependence.

• Bulletin of the Korean Chemical Society
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• v.30 no.3
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• pp.599-607
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• 2009

A series of conjugated cyclic and linear enkephalin analogs, Tyr-c[D-A2bu-Gly-Phe-Asp(NH-X)], where X = methyl, stearyl or$ PEG_350$, and Tyr-D-Ala-Gly-Phe-Cys(S-X), where X = methyl, octyl, or farnesyl, were synthesized in solution to investigate the receptor selectivity of opioids based on Schwyzer's membrane compartment $concepts.^{5,6}$ Cyclizations of the target compounds were achieved in high yields (> 60%) employing BOP, $NaHCO_3$ in DMF despite the steric hindrance of the bulky pendant groups. In the binding assay, the hydrophobic fatty acyl conjugates retained $\mu$-receptor selectivity. The unsaturated farnesyl conjugate exhibited the increased binding affinity than the saturated stearyl conjugate for both $\mu$-and $\delta$-opioid receptors. The PEG conjugates displayed the $\delta$-receptor selectivity. The low molecular weight $PEG_350$ conjugate exhibited the increase selectivity than the high molecular weight $PEG_5000$ conjugate to the $\delta$-receptor. The results of this study support the membrane compartment concepts.

• The Korean Journal of Physiology and Pharmacology
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• v.16 no.3
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• pp.187-192
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• 2012

In the present study, the antinociceptive profiles of hop extract were characterized in ICR mice. Hop extract administered orally (from 25 to 100 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test. Antinociceptive action of hop extract was maintained at least for 60 min. Moreover, cumulative response time of nociceptive behaviors induced with intraplantar formalin injection was reduced by hop extract treatment during the 2nd phases. Furthermore, the cumulative nociceptive response time for intrathecal injection of substance P ($0.7{\mu}g$) or glutamate ($20{\mu}g$) was diminished by hop extract. Intraperitoneal pretreatment with naloxone (an opioid receptor antagonist) attenuated antinociceptive effect induced by hop extract in the writhing test. However, methysergide (a 5-HT serotonergic receptor antagonist) or yohimbine (an ${\alpha}_2$-adrenergic receptor antagonist) did not affect antinociception induced by hop extract in the writhing test. Our results suggest that hop extract shows an antinociceptive property in various pain models. Furthermore, the antinociceptive effect of hop extract may be mediated by opioidergic receptors, but not serotonergic and ${\alpha}_2$-adrenergic receptors.

• The Korean Journal of Pharmacology
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• v.30 no.3
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• pp.291-297
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• 1994

Our purpose was to gain insight into a possible modulatory role for ${\mu},\;{\delta},\;and\;{\kappa}$ opioid receptors by neuroleptics (chlorpromazine, thioridazine, haloperidol, sulpiride, and pimozide) in chronic morphine 5 mg/kg and 20 mg/kg treated mouse striatum. We attempted quantitative receptor assays using highly specific radioligands, $[^3H]\;DAGO\;([D-Ala^2,\;N-Mephe^4,\;Glycol^5]\;enkephalin)$, $[^3H]DPDPE\;([D-Pen^2,\;D-Pen^5]\;enkephalin)$ and $[^3H]\;DPN(diprenorphine)$ to measure the binding affinity in the experimental groups. The decrease of $[^3H]DAGO$ binding was potentiated by sulpiride and pimozide in the chronic morphine treatment (5 mg/kg and 20 mg/kg). The decrease of $[^3H]DPDPE$ binding was inhibited by chlorpromazine, thioridazine, haloperidol, sulpiride, and pimozide in chronic morphine treatment (5 mg/kg and 20 mg/kg). The decrease of $[^3H]\;DPN$ binding was significantly inhibited by chlorpromazine, thioridazine, sulpiride, and pimozide in chronic morphine 20 mg/kg treatment. $[^3H]\;DPN$ binding on the neuroleptics was antagonized by naloxone pretreatment in chronic morphine 20 mg/kg treatment. These findings suggest that neuroleptics influence opposing tonically active on the ${\delta},\;and\;{\kappa}$ opioid receptor compared with ${\mu}$ opioid receptor in the chronic morphine treated mouse striatum.

• Biomolecules & Therapeutics
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• v.26 no.2
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• pp.101-108
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• 2018

G protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane receptors and have vital signaling functions in various organs. Because of their critical roles in physiology and pathology, GPCRs are the most commonly used therapeutic target. It has been suggested that GPCRs undergo massive genetic variations such as genetic polymorphisms and DNA insertions or deletions. Among these genetic variations, non-synonymous natural variations change the amino acid sequence and could thus alter GPCR functions such as expression, localization, signaling, and ligand binding, which may be involved in disease development and altered responses to GPCR-targeting drugs. Despite the clinical importance of GPCRs, studies on the genotype-phenotype relationship of GPCR natural variants have been limited to a few GPCRs such as b-adrenergic receptors and opioid receptors. Comprehensive understanding of non-synonymous natural variations within GPCRs would help to predict the unknown genotype-phenotype relationship and yet-to-be-discovered natural variants. Here, we analyzed the non-synonymous natural variants of all non-olfactory GPCRs available from a public database, UniProt. The results suggest that non-synonymous natural variations occur extensively within the GPCR superfamily especially in the N-terminus and transmembrane domains. Within the transmembrane domains, natural variations observed more frequently in the conserved residues, which leads to disruption of the receptor function. Our analysis also suggests that only few non-synonymous natural variations have been studied in efforts to link the variations with functional consequences.

• The Korean Journal of Pharmacology
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• v.28 no.2
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• pp.181-190
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• 1992

The present study was conducted to investigate the effect of opioids on catecholamine (CA) secretion evoked by a selective cholinergic nicotinic agonist, 1,1-dimethyl-4-phenyl piperazinium (DMPP) and acetylcholine from the retrogradely perfused rat adrenal glands. Methionine-enkephalin $(9.68{\times}10^{-6}\;M)$ caused a significant inhibition of CA secretion evoked by DMPP (100 uM) and $ACh\;(50\;{\mu}g)$, but had no effect on the spontaneous (basal) CA release. Morphine $(1.73{\times}10^{-5}\;M)$ attenuated considerablely the increase in CA release induced by DMPP and ACh. Morphine itself also did not affect the basal CA output. A 20 to 65% reduction of the DMPP- and ACh-evoked increase in CA release was observed after the pretreatment with methionine-enkephalin or morphine. The increase in CA release evoked by DMPP and ACh was reduced markedly by preloading with an opiate antagonist naloxone $(1.22{\times}10^{-7}\;M)$ while basal CA output was not affected by naloxone. These present experimental results suggest that the nicotinic stimulation-evoked CA release from the perfused rat adrenal gland is inhibited by endogenously released opioid peptides through activation of opiate receptors located in the adrenal gland.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2005.11a
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• pp.49-66
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• 2005

Panax ginseng has been useful for the treatment of diverse disease in oriental countries for thousands of years. In addition, a folk medicine prescribed by seven herbal drugs including Panax ginseng has been antinarcotics in the treatment of morphine-dependent patients. Many articles have been reported on these works. Therefore, we review the protective effects of Panax ginseng on the neurotoxicity induced by abuse drugs. Ginseng total saponins (GTS) extracted and isolated by Panax ginseng antagonized Morphine-induced analgesia, and inhibited the development of analgesic tolerance to and physical dependence on morphine. GTS inhibited morphine-6 dehydrogenase, which catalyzes production of mophinone from morphine, and increased hepatic glutathione level responsible to toxicity. Therefore, we hypothesized that these dual actions of ginseng can be associated with the detoxication of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contraction in guinea pig ileum ($\mu$-receptors) and mouse vas deferens($\delta$-receptors) were not mediated through opioid receptors, suggesting non-opioid mechanisms. On the hand, antagonism of U-50,488H ($\kappa$-agonist)-induced antinociception is mediated by serotonergic mechanisms. GTS also inhibited hyperactivity, reverse tolerance (sensitization) and conditioned place preference-induced by psychostimulants such as methamphetamine, cocaine and morphine. On the other hand, GTS reduced the dopamine levels induced by methamphetamine. Moreover, GTS blocked the development of dopamine receptor activation, showing antidopaminergic effect. We suggest that GTS Prevent the methamphetamine-induced striatal dopaminergic neurotoxicity. In addition, Ginsenoside also attenuates morphine-induced cAMP signaling pathway. These results suggested that GTS might be useful for the therapy of the adverse actions of drugs with abuse liability.

• Proceedings of the Ginseng society Conference
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• 2005.11a
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• pp.41-63
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• 2005

Ginseng has been useful for the treatment of diverse disease in oriental countries for thousands of years. In addition, a folk medicine prescribed by seven herbal drugs including Panax ginseng has been antinarcotics in the treatment of morphine-dependent patients. Many articles have been reported on these works. Therefore, we review the protective effects of Panax ginseng on the neurotoxicity induced by abuse drugs. Ginseng total saponins (GTS) extracted and isolated by Panax ginseng antagonized morphine-induced analgesia, and inhibited the development of analgesic tolerance to and physical dependence on morphine. CTS inhibited morphine-6 dehydrogenase, which catalyzes production of mophinone from morphine, and increased hepatic glutathione level responsible to toxicity. Therefore, wehypothesized that these dual actions of ginseng can be associated with the detoxication of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contraction in guinea pig ileum (${\mu}$-receptors) and mouse vas deferens(${\delta}$-receptors) were not mediated through opioid receptors, suggesting non-opioid mechanisms. On the hand, antagonism of U-50,488H (${\kappa}$-agonist)-induced antinociception is mediated by serotonergic mechanisms. GTS also inhibited hyperactivity, reverse tolerance (sensitization) and conditioned place preference-induced by psychostimulants such as methamphetamine, cocaine and morphine. On the other hand, GTS reduced the dopamine levels induced by methamphetamine. Moreover, GTS blocked the development of dopamine receptor activation, showing antidopaminergic effect. We suggest that GTS prevent the methamphetamine-induced striatal dopaminergic neurotoxicity. In addition, Ginsenoside also attenuates morphine-induced CAMP signaling pathway. These results suggested that GTS might be useful for the therapy of the adverse actions of drugs with abuse liability.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.04a
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• pp.305-305
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• 1994

It has been shown that there are several subtypes of $\kappa$ opioid receptor, We have evaluated the properties of non-${\mu}$, non-$\delta$ binding of 〔$^3$H〕DIP, a nonselective opioid antagonist, in rat cortex membranes. Binding to ${\mu}$ and $\delta$ sites was inhibited by the use of an excess of competing selective agonists (DAMGO, DPDPE) for these sites. (-)Ethylketocyclazocine(EKC) inhibited 〔$^3$H〕DIP binding with Ki. of 70 nM. However, arylacetamides (U69593 and U50488H) gave little inhibition. Also, we have examined the opioid modulation of K$\^$+/(30 mM)-induced histamine release in rat frontal cortex slices labeled with 1-〔$^3$H〕histidine. The 〔$^3$H〕histamine release from cortex slices was inhibited by EKC, a $\kappa$$_1$-and $\kappa$$_2$-agonist, in a concentration-dependent manner(10 to 10,000 nM). The IC$\sub$50/ of EKC was 107 ${\pm}$ 6 nM. However, the $\delta$ receptor selective agonists, DPDPE and deltorphine II, ${\mu}$ receptor agonists, DAMGO and TAPS, $\kappa$$_1$-agonists, U69593 and U50488H, and $\varepsilon$-agonist, ${\beta}$-endorphin, did not inhibit histamine release even in micromoiar dose, indicating that ${\mu}$, $\delta$ or $\kappa$$_1$ receptors are not involved. The concentration-response curve of EKC was shifted to right in the presence of naloxone (300 nM), a ${\mu}$ preferential antagonist, norbinaltorphimine(300 nM), a $\kappa$$_1$ preferential antagonist and bremazocine(1 nM), a $\kappa$$_1$-agonist and $\kappa$$_2$-antagonist. These results suggest that $\kappa$$_2$ opioid receptor regulates histamine release in the frontal cortex of the rat.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.4
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• pp.419-425
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• 2018

The superficial dorsal horn of the spinal cord plays an important role in pain transmission and opioid activity. Several studies have demonstrated that opioids modulate pain transmission, and the activation of ${\mu}$-opioid receptors (MORs) by opioids contributes to analgesic effects in the spinal cord. However, the effect of the activation of MORs on GABAergic interneurons and the contribution to the analgesic effect are much less clear. In this study, using transgenic mice, which allow the identification of GABAergic interneurons, we investigated how the activation of MORs affects the excitability of GABAergic interneurons and synaptic transmission between primary nociceptive afferent and GABAergic interneurons. We found that a selective ${\mu}$-opioid agonist, [$D-Ala^2$, $NMe-Phe^4$, Gly-ol]-enkephanlin (DAMGO), induced an outward current mediated by $K^+$ channels in GABAergic interneurons. In addition, DAMGO reduced the amplitude of evoked excitatory postsynaptic currents (EPSCs) of GABAergic interneurons which receive monosynaptic inputs from primary nociceptive C fibers. Taken together, we found that DAMGO reduced the excitability of GABAergic interneurons and synaptic transmission between primary nociceptive C fibers and GABAergic interneurons. These results suggest one possibility that suppression of GABAergic interneurons by DMAGO may reduce the inhibition on secondary GABAergic interneurons, which increase the inhibition of the secondary GABAergic interneurons to excitatory neurons in the spinal dorsal horn. In this circumstance, the sum of excitation of the entire spinal network will control the pain transmission.