• Archives of Pharmacal Research
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• 제25권2호
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• pp.202-207
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• 2002

This study was performed to investigate the effect of tetrahydroisoxazolopyridine (THIP), a $GABA_A$ agonist, on the morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice. A single administration of morphine induced hyperactivity in mice. However, the morphine-induced hyperactivity was inhibited dose-dependently by the administration of THIP (0.2, 0.4 and 0.8 mg/kg, i.p.). In contrast, daily administration of morphine resulted in a reverse tolerance to the hyperactivity caused by morphine (10 mg/kg ,s.c.). THIP inhibited the development of reverse tolerance in the mice that had received the repeated same morphine (10 mg/kg s.c.) doses. The postsynaptic dopamine receptor supersensitivity, which was evidenced by the enhanced ambulatory activity its after the administration of apomorphine (2 mg/kg s.c.), also developed in the reverse tolerant mice. THIP also inhibited the development of the postsynaptic dopamine receptor supersensitivity indulged by the chronic morphine administration. These results suggest that the hyperactivity, reverse toterance and postsynaptic dopamine receptor supersensitivity induced by morphine can be inhibited activating the $GABA_A$ receptors.

• Food Science and Biotechnology
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• 제27권6호
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• pp.1833-1842
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• 2018

The aim of this study was to identify sleep-promoting substance from Polygonatum sibiricum rhizome extract (PSE) with the regulation of sleep architecture. PSE showed a decrease in sleep latency time and an increase in the sleeping time. In the electroencephalography analysis of rats, PSE (150 mg/kg) showed an increase of non-rapid eye movement by 38% and a decrease of rapid eye movement by 31% compared to the control. This sleep-promoting activity was found to be involved in the $GABA_A$-BDZ receptor. The chemical structure of the pure compound was determined by the $^1H$ and $^{13}C$ nuclear magnetic resonance spectroscopy and gas chromatography mass spectrometry analysis; active compound was glyceryl-1-monolinoleate. The commercial standard glyceryl-1-monolinoleate showed a similar inhibitory concentration on [$^3H$]-flumazenil binding to $GABA_A$-BDZ receptors with final active fraction of PSE. The results indicate that glyceryl-1-monolinoleate is a major active compound responsible for the PSE-derived sleep promotion.

• 대한화장품학회지
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• 제44권3호
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• pp.277-284
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• 2018

콜라겐 펩타이드(collagen peptide)는 단백질의 가수 분해물로서 주름 완화, 보습력 증대, 탄력 개선 등의 특정 피부 효능을 나타낼 수 있어 화장품 혹은 피부 개선 기능식품으로서 활용되고 있다. ${\gamma}-aminobutyric$ acid (GABA)는 척추 동물의 뇌, 척수에 존재하는 신경전달 물질로서 수면의 질과 양을 개선해 준다고 알려져 있다. 본 연구에서는 콜라겐 펩타이드와 GABA의 복합물이 수면 장애가 있는 여성에게 8주 경구 섭취를 통해서 수면 및 피부 상태를 개선할 수 있는가에 관하여 확인하였다. 복합물(J85091900)은 8주간 연속적으로 섭취 시, 수면장애지수(PSQI)가 유의적으로 감소하였으며, 수면 시간을 7% 증가시켰다. 또한, 피부 거칠기, 눈가 주름 및 피부 수분량(capacitance)을 유의적으로 개선하였다. 이상의 결과에서 콜라겐과 GABA의 복합물은 복합 수면 장애에 따른 피부의 노화 현상으로부터 피부를 보호할 수 있음을 확인하여 먹는 화장품의 핵심 소재로 활용 가능함을 확인하였다.

• 대한약리학회지
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• 제29권1호
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• pp.23-32
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• 1993

GABA계가 뇌내의 교감신경계기능에 영향을 주어서 혈압조절에 관여함이 알려져 있다. 본 연구에서는 마취가토에서 GABA계가 두개내압증가에 의한 혈압상승에 관여하는가를 조사하였다. 두개내압증가에 의한 승압은 측뇌실내 muscimol (GABA 작용약)이나 clonidine $({\alpha}_2$-작용약) 전처리후에는 볼 수 없었다. 측뇌실내 yohimbine $({\alpha}_2$-길항약)으로 일으킨 고혈압은 두개내압증가를 하여도 더 이상 상승하지 않았으나, 측뇌실내 bicuculline (GABA 길항약)으로 일으킨 고혈압은 두개내압증가로 더욱 상승하였다. Bicuculline은 muscimol이나 clonidine 저혈압에서는 승압을 일으켰으나 yohimbine이나 두개내압증가에 의한 고혈압에서는 무효였다. Yohimbine은 clonidine 저혈압은 상승시켰으나 muscimol 저혈압에 있어서는 무효였다. Yohimbine은 두개내압증가에 따른 승압상태는 더 올리지 못하였으나 bicuculline 승압상태는 더욱 상승시켰다. Muscimol은 bicuculline과의 길항성이외에 yohimbine 승압을 억제함을 알았으며 yohimbine 승압에 GABA계가 관여함을 추측할 수 있었다. 이러한 실험결과로 두개내압증가에 따른 승압상승은 (1) ${\alpha}_{2}$-수용체, (2) bicuculline-감수성 GABA 수용체, (3) yohimbine-감수성인 clonidine이 작용하는 GABA계 부위의 세가지 방법으로 억제성인 교감신경기능을 불활성화하여 일어나는 것으로 추론하였다.

• Journal of Yeungnam Medical Science
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• 제9권2호
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• pp.359-381
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• 1992

Benzodiazepine계 약물들은 진정 최면제의 대표적인 약물로서, 중추신경계에서의 그 작용은 gamma amino butyric acid(GABA) 수용체와 짝지워져 있는 benzodiazepine 수용체를 통해서 나타나며 또한 뇌에 있는 synaptosome에서 전위 의존성 calcium channel을 통한 calcium의 섭취를 억제함으로써 진정작용 및 최면 작용이 나타난다. 이와 아울러 말초 장기에서도 benzodiazepine 수용체와 GABA 수용체가 발견 되었는데 이들의 기능과 상호관계는 잘 알려져 있지 않다. 이에 본 실험에서는 benzodiazepine계통의 대표적인 약물이며 중추신경과 말초 장기에 동시에 작용하는 diazepam이 흰쥐 적출자궁의 자발 수축 및 oxytocin 유발 수축에 미치는 영향을 검색하고, 이러한 diazepam의 효과와 GABA 수용체 및 calcium과의 상호관계를 검색함으로써 그 작용기전을 추구해 보기 위하여 다음과 같은 실험을 하였다. 난소를 제거한 후 estrogen(17 beta-estradiol : $500{\mu}g/kg/day$)을 4일 동안 전 처치한 흰쥐의 자궁을 적출하여 등척성 장력을 측정함으로써 그 수축력의 변화를 관찰하였다. Diazepam과 GABA 수용체 효현제 및 그 봉쇄제들이 자궁절편의 자발 수축과 oxytocin 유발 수축에 미치는 영향을 검색하였고, 또 이들 약물의 작용에 관련된 calcium 동원기전에 대하여 관찰하여 다음과 같은 결과를 얻었다. Diazepam은 흰쥐 적출자궁의 자발수축 및 oxytocin 유발수축을 농도 의존적으로 억제하였다. GABA, GABA A 수용체 효현제인 muscimol, GAGA A 수용체의 상경적 봉쇄제인 bicuculline, GABA A 수용체의 비상경적 봉쇄제인 picrotoxin, GABA B 수용체 효현제인 boclofen, 그리고 GABA B 수용체 봉쇄제인 delta-aminovaleric acid는 흰쥐 적출 자궁의 자발 수축 및 oxytocin 유발수축에 아무런 영향을 미치지 않았다. 자발 수축 및 oxytocin 유발수축에 대한 diazepam의 억제 작용은 GABA 수용체 효현제 및 봉쇄제의 영향을 받지 않았다. 그러나 bicuculline은 diazepam의 억제 작용에 상가적으로 작용하였는데, bicuculline의 이러한 작용은 muscimol에 의해서 길항되지 않았다. 정상 PSS 내에서 diazepam에 의해 억제되었던 자발수욱 및 oxytocin유발수촉은 calcium의 첨가 및 calcium inophore인 A23187의 첨가로 일부 회복되었다. Calcium 배제 용액내에서는 diazepam이 calcium 첨가로 인한 수축력 회복을 방해하였으며 calcium inophore인 A23187에 의한 수축력 증가는 막지 못하였다. 또 세포외액에 calcium이 결핍된 상태에서는 oxytocin 자체에 의한 수축을 방해하지 못하였으나 이어 첨가된 calcium에 의한 oxytocin 유발 수축의 증가는 일부 억제하였다. 이상의 실험결과로 미루어 볼 때 diazepam은 자궁의 자발수측 및 oxytocin 유발 수축을 억제할 수 있으며, 이러한 작용은 GABA 수용체 의존성이 아닌 세포외액의 calcium의 유입을 억제함으로써 나타나는 것으로 사료된다.

• Journal of Ginseng Research
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• 제34권4호
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• pp.304-313
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• 2010

This study was undertaken to discover the effects and possible mechanisms of the effect of red ginseng extract (RGE) on spontaneous sleep. The effects of a low dose (10 mg/kg) and a high dose (200 mg/kg) of RGE were compared in rats. After recovery from a surgical operation enabling electroencephalograms recordings, rats were administered RGE orally. RGE was administered orally for 1 day or once per day for 5 days in either 10 or 200 mg/kg doses. Polygraphic signs were recorded for 12 h after oral administration of RGE. Both treatment with a large dose (200 mg/kg) of RGE for one day and treatment with either a large or a small dose for 5 days reduced the number of sleep.wake cycles. Daily treatment with RGE (either 10 or 200 mg/kg) for 5 days augmented NREM and total sleep, but reduced wakefulness. Delta wave activity recorded during non-REM (NREM) sleep and REM sleep was increased after one treatment with RGE (either 10 or 200 mg/kg). Delta wave activity during NREM was enhanced after daily treatment with RGE (either 10 or 200 mg/kg) for 5 days. Both alpha and beta subunits of the $\gamma$-aminobutyric acid $(GABA)_A$ receptor were significantly over-expressed in the hypothalamus of the RGE-treated groups. Moreover, the expression of glutamic acid decarboxylase was also increased in the hypothalamus. These results demonstrate that RGE may regulate spontaneous sleep via $GABA_A$ergic systems.

• The Korean Journal of Pain
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• 제32권3호
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• pp.160-167
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• 2019

Background: Pain is a complex mechanism which involves different systems, including the opioidergic and GABAergic systems. Due to the side effects of chemical analgesic agents, attention toward natural agents have been increased. Artemisinin is an herbal compound with widespread modern and traditional therapeutic indications, which its interaction with the GABAergic system and antinoniceptive effects on neuropathic pain have shown. Therefore, this study was designed to evaluate the antinociceptive effects of artemisinin during inflammatory pain and interaction with the GABAergic and opioidergic systems by using a writhing response test. Methods: On the whole, 198 adult male albino mice were used in 4 experiments, including 9 groups (n = 6) each with three replicates, by intraperitoneal (i.p.) administration of artemisinin (2.5, 5, and 10 mg/kg), naloxone (2 mg/kg), bicuculline (2 mg/kg), saclofen (2 mg/kg), indomethacin (5 mg/kg), and ethanol (10 mL/kg). Writhing test responses were induced by i.p. injection of 10 mL/kg of 0.6% acetic acid, and the percentage of writhing inhibition was recorded. Results: Results showed significant dose dependent anti-nociceptive effects from artemisinin which, at a 10 mg/kg dose, was statistically similar to indomethacin. Neither saclofen nor naloxone had antinociceptive effects and did not antagonize antinociceptive effects of artemisinin, whereas bicuculline significantly inhibited the antinocicptive effect of artemisinin. Conclusions: It seems that antinocicptive effects of artemisinin are mediated by $GABA_A$ receptors.

• The Korean Journal of Pain
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• 제37권3호
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• pp.218-232
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• 2024

Background: Cynara scolymus has bioactive constituents and has been used for therapeutic actions. The present study was undertaken to investigate the mechanisms underlying pain-relieving effects of the hydroethanolic extract of C. scolymus (HECS). Methods: The antinociceptive activity of HECS was assessed through formalin and acetic acid-induced writhing tests at doses of 50, 100 and 200 mg/kg intraperitoneally. Additionally, naloxone (non-selective opioid receptors antagonist, 2 mg/kg), atropine (non-selective muscarinic receptors antagonist, 1 mg/kg), chlorpheniramine (histamine H₁-receptor antagonist, 20 mg/kg), cimetidine (histamine H₂-receptor antagonist, 12.5 mg/kg), flumazenil (GABA_A/BDZ receptor antagonist, 5 mg/kg) and cyproheptadine (serotonin receptor antagonist, 4 mg/kg) were used to determine the systems implicated in HECS-induced analgesia. Impact of HECS on locomotor activity was executed by open-field test. Determination of total phenolic content (TPC) and total flavonoid content (TFC) was done. Evaluation of antioxidant activity was conducted employing 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay. Results: HECS (50, 100 and 200 mg/kg) significantly indicated dose dependent antinociceptive activity against pain-related behavior induced by formalin and acetic acid (P < 0.001). Pretreatment with naloxone, atropine and flumazenil significantly reversed HECS-induced analgesia. Antinociceptive effect of HECS remained unaffected by chlorpheniramine, cimetidine and cyproheptadine. Locomotor activity was not affected by HECS. TPC and TFC of HECS were 59.49 ± 5.57 mgGAE/g dry extract and 93.39 ± 17.16 mgRE/g dry extract, respectively. DPPH free radical scavenging activity (IC₅₀) of HECS was 161.32 ± 0.03 ㎍/mL. Conclusions: HECS possesses antinociceptive activity which is mediated via opioidergic, cholinergic and GABAergic pathways.

• The Korean Journal of Physiology and Pharmacology
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• 제14권2호
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• pp.59-69
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• 2010

Impairment in spinal inhibition caused by quantitative alteration of GABAergic elements following peripheral nerve injury has been postulated to mediate neuropathic pain. In the present study, we tested whether neuropathic pain could be induced or reversed by pharmacologically modulating spinal GABAergic activity, and whether quantitative alteration of spinal GABAergic elements after peripheral nerve injury was related to the impairment of GABAergic inhibition or neuropathic pain. To these aims, we first analyzed the pain behaviors following the spinal administration of GABA antagonists ($1{\mu}g$ bicuculline/rat and $5{\mu}g$ phaclofen/rat), agonists ($1{\mu}g$ muscimol/rat and $0.5{\mu}g$ baclofen/rat) or GABA transporter (GAT) inhibitors ($20{\mu}g$ NNC-711/rat and $1{\mu}g$ SNAP-5114/rat) into naive or neuropathic animals. Then, using Western blotting, PCR or immunohistochemistry, we compared the quantities of spinal GABA, its synthesizing enzymes (GAD65, 67) and its receptors (GABAA and GABAB) and transporters (GAT-1, and -3) between two groups of rats with different severity of neuropathic pain following partial injury of tail-innervating nerves; the allodynic and non-allodynic groups. Intrathecal administration of GABA antagonists markedly lowered tail-withdrawal threshold in naive animals, and GABA agonists or GAT inhibitors significantly attenuated neuropathic pain in nerve-injured animals. However, any quantitative changes in spinal GABAergic elements were not observed in both the allodynic and non-allodynic groups. These results suggest that although the impairment in spinal GABAergic inhibition may play a role in mediation of neuropathic pain, it is not accomplished by the quantitative change in spinal elements for GABAergic inhibition and therefore these elements are not related to the generation of neuropathic pain following peripheral nerve injury.

• Molecules and Cells
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• 제20권3호
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• pp.305-314
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• 2005

Investigation of chemically synthesized inositol 1,4,5-trisphosphate [$Ins(1,4,5)P_3$] analogs has led to the isolation of a novel binding protein with a molecular size of 130 kDa, characterized as a molecule with similar domain organization to phospholipase C-${\delta}1$ (PLC-${\delta}1$) but lacking the enzymatic activity. An isoform of the molecule was subsequently identified, and these molecules have been named PRIP (PLC-related, but catalytically inactive protein), with the two isoforms named PRIP-1 and -2. Regarding its ability to bind $Ins(1,4,5)P_3$ via the pleckstrin homology domain, the involvement of PRIP-1 in $Ins(1,4,5)P_3$-mediated $Ca^{2+}$ signaling was examined using COS-1 cells overexpressing PRIP-1 and cultured neurons prepared from PRIP-1 knock-out mice. Yeast two hybrid screening of a brain cDNA library using a unique N-terminus as bait identified GABARAP ($GABA_A$ receptor associated protein) and PP1 (protein phosphatase 1), which led us to examine the possible involvement of PRIP in $GABA_A$ receptor signaling. For this purpose PRIP knock-out mice were analyzed for $GABA_A$ receptor function in relation to the action of benzodiazepines from the electrophysiological and behavioral aspects. During the course of these experiments we found that PRIP also binds to the b-subunit of $GABA_A$ receptors and PP2A (protein phosphtase 2A). Here, we summarize how PRIP is involved in $Ins(1,4,5)P_3$-mediated $Ca^{2+}$ signaling and $GABA_A$ receptor signaling based on the characteristics of binding molecules.