• The Korean Journal of Physiology and Pharmacology
• /
• v.7 no.3
• /
• pp.169-174
• /
• 2003

${\gamma}$-Aminobutyric acid (GABA) has been reported to enhance exocrine secretion evoked not only by secretagogues but also by intrinsic neuronal excitation in the pancreas. The pancreas contains cholinergic neurons abundantly that exert a stimulatory role in exocrine secretion. This study was undertaken to examine effects of GABA on an action of cholinergic neurons in exocrine secretion of the pancreas. Intrinsic neurons were excited by electrical field stimulation (EFS; 15 V, 2 msec, 8 Hz, 45 min) in the isolated, perfused rat pancreas. Tetrodotoxin or atropine was used to block neuronal or cholinergic action. Acetylcholine was infused to mimic cholinergic excitation. GABA $(30{\mu}M)$ and muscimol $(10{\mu}M)$, given intra-arterially, did not change spontaneous secretion but enhanced cholecystokinin (CCK; 10 pM)-induced secretions of fluid and amylase. GABA (3, 10, $30{\mu}M$) further elevated EFS-evoked secretions of fluid and amylase dose-dependently. GABA (10, 30, $100{\mu}M$) also further increased acetylcholine $(5{\mu}M)$-induced secretions of fluid and amylase in a dose-dependent manner. Bicuculline $(10{\mu}M)$ effectively blocked the enhancing effects of GABA $(30{\mu}M)$ on the pancreatic secretions evoked by either EFS or CCK. Both atropine $(2{\mu}M)$ and tetrodotoxin $(1{\mu}M)$ markedly reduced the GABA $(10{\mu}M)$-enhanced EFS- or CCK-induced pancreatic secretions. The results indicate that GABA enhances intrinsic cholinergic neuronal action on exocrine secretion via the $GABA_A$ receptors in the rat pancreas.

• Biomolecules & Therapeutics
• /
• v.25 no.2
• /
• pp.105-111
• /
• 2017

It has been known that RA, one of major constituents of Perilla frutescens which has been used as a traditional folk remedy for sedation in oriental countries, shows the anxiolytic-like and sedative effects. This study was performed to know whether RA may enhance pentobarbital-induced sleep through ${\gamma}-aminobutyric$ acid $(GABA)_A-ergic$ systems in rodents. RA (0.5, 1.0 and 2.0 mg/kg, p.o.) reduced the locomotor activity in mice. RA decreased sleep latency and increased the total sleep time in pentobarbital (42 mg/kg, i.p.)-induced sleeping mice. RA also increased sleeping time and number of falling sleep mice after treatment with sub-hypnotic pentobarbital (28 mg/kg, i.p.). In electroencephalogram (EEG) recording, RA (2.0 mg/kg) not only decreased the counts of sleep/wake cycles and REM sleep, but also increased the total and NREM sleep in rats. The power density of NREM sleep showed the increase in ${\delta}-waves$ and the decrease in ${\alpha}-waves$. On the other hand, RA (0.1, 1.0 and $10{\mu}g/ml$) increased intracellular $Cl^-$ influx in the primary cultured hypothalamic cells of rats. RA (p.o.) increased the protein expression of glutamic acid decarboxylase ($GAD_{65/67}$) and $GABA_A$ receptors subunits except ${\beta}1$ subunit. In conclusion, RA augmented pentobarbital-induced sleeping behaviors through $GABA_A-ergic$ transmission. Thus, it is suggested that RA may be useful for the treatment of insomnia.

• The Korean Journal of Pain
• /
• v.20 no.2
• /
• pp.100-105
• /
• 2007

Background: Ginseng has been used to manage various types of pain in folk medicine. This study characterized the effect of treatment with intrathecal ginsenosides, the active components of ginseng in a postoperative pain model. Methods: Male Sprague-Dawley rats were implanted with lumbar intrathecal catheters. An incision was made in the plantar surface of the hindpaw. Withdrawal thresholds following the application of a von Frey filament to the wound site were measured. To determine the role of the opioid or GABA receptors following treatment with the ginsenosides, naloxone, bicuculline (a $GABA_A$ receptor antagonist), and saclofen (a $GABA_B$ receptor antagonist) were administered intrathecally 10 min before the delivery of the ginsenosides and the changes of the withdrawal thresholds after application of the von Frey filament were Observed. Results: Treatment with the intrathecal ginsenosides increased the withdrawal threshold in a dose dependent manner. Pre-treatment with intrathecal naloxone reversed the antinociceptive effect of the ginsenosides. However, pre-treatment with intrathecal bicuculline and saclofen failed to have an effect on the activity of the ginsenosides. Conclusions: These results suggest that ginsenosides are effective to alleviate the postoperative pain evoked by paw incision. The opioid receptor, but not GABA receptors, may be involved in the antinociceptive action of the ginsenosides at the spinal level.

• Natural Product Sciences
• /
• v.21 no.3
• /
• pp.219-225
• /
• 2015

In the previous experiments, we reported that ethanol extract of Gastrodiae Rhizoma, the dried tuber of Gastrodia ElataBlume (Orchidaceae) increased pentobarbital-induced sleeping behaviors. These experiments were undertaken to know whether 4-hydroxybenzaldehyde (4-HBD), is one of the major compounds of Gastrodiae Rhizoma increases pentobarbital-induced sleeping behaviors and changes sleep architectures via activating GABA_A-ergic systems in rodents. 4-HBD decreased locomotor activity in mice. 4-HBD increased total sleep time, and decreased of sleep onset by pentobarbital (28 mg/kg and 40 mg/kg). 4-HBD showed synergistic effects with muscimol (a GABA_A receptor agonist), shortening sleep onset and enhancing sleep time on pentobarbital-induced sleeping behaviors. On the other hand, 4-HBD (200 mg/kg, p.o.) itself significantly inhibited the counts of sleepwake cycles, and prolonged total sleep time and non-rapid eye movement (NREM) in rats. Moreover, 4-HBD increased intracellular Cl⁻ levels in the primary cultured cerebellar cells. The protein levels of glutamic acid decarboxylase (GAD) and GABA_A receptors subunits were over-expressed by 4-HBD. Consequently, these results demonstrate that 4-HBD increased NREM sleep as well as sleeping behaviors via the activation of GABA_A-ergic systems in rodents.

• Journal of Dental Anesthesia and Pain Medicine
• /
• v.23 no.3
• /
• pp.153-162
• /
• 2023

Background: Recent animal studies have suggested the role of GABA type A (GABA-_A) receptors in salivation, showing that GABA-_A receptor agonists inhibit salivary secretion. This study aimed to evaluate the effects of propofol (a GABA-_A agonist) on salivary secretions from the submandibular, sublingual, and labial glands during intravenous sedation in healthy volunteers. Methods: Twenty healthy male volunteers participated in the study. They received a loading dose of propofol 6 mg/kg/h for 10 min, followed by 3 mg/kg/h for 15 min. Salivary flow rates in the submandibular, sublingual, and labial glands were measured before, during, and after propofol infusion, and amylase activity was measured in the saliva from the submandibular and sublingual glands. Results: We found that the salivary flow rates in the submandibular, sublingual, and labial glands significantly decreased during intravenous sedation with propofol (P < 0.01). Similarly, amylase activity in the saliva from the submandibular and sublingual glands was significantly decreased (P < 0.01). Conclusion: It can be concluded that intravenous sedation with propofol decreases salivary secretion in the submandibular, sublingual, and labial glands via the GABA-_A receptor. These results may be useful for dental treatment when desalivation is necessary.

• The Korean Journal of Food And Nutrition
• /
• v.30 no.6
• /
• pp.1364-1369
• /
• 2017

There is a growing demand for natural sleep aids due to various side effects of long-term administration of pharmacological treatments for insomnia. Honey has been reported to exhibit numerous potential health benefits, and it is hypothesized that honey may favorably affect insomnia treatment. Therefore, this study was performed to investigate the possible hypnotic effect of clover honey (CH) and to determine its in vivo mechanism. The total flavonoid content (TFC) of CH and fractions extracted with ethylacetate (EtOAc) and $H_2O$ was measured. The pentobarbital-induced sleep test using $GABA_A$-benzodiazepine (BZD) agonists and antagonists was conducted to evaluate the potential mechanism of action behind the sedative-hypnotic activity of CH in mice. The results showed that administration of 500 and 1,000 mg/kg of CH significantly (p<0.01) reduced the sleep latency to a level similar to that of diazepam (DZP, 2 mg/kg), and 1,000 mg/kg of CH significantly (p<0.01) prolonged the sleep duration, which was comparable to that of DZP (2 mg/kg). Administration of the EtOAc fraction with a higher TFC significantly reduced the sleep latency at 50 to 200 mg/kg and prolonged the sleep duration at 100 to 200 mg/kg, which were comparable to those after administration of DZP (2 mg/kg). However, co-administration of CH and EtOAc with flumazenil, a specific $GABA_A-BZD$ receptor antagonist, blocked the hypnotic effect. Our findings suggest that the hypnotic activity of CH may be attributed to allosteric modulation of $GABA_A-BZD$ receptors. The TFC of CH is expected to be a key factor that contributes to its hypnotic effect.

• Food Science and Biotechnology
• /
• v.27 no.6
• /
• pp.1833-1842
• /
• 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.

• Archives of Pharmacal Research
• /
• v.25 no.2
• /
• pp.202-207
• /
• 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.

• The Korean Journal of Pharmacology
• /
• v.29 no.1
• /
• pp.23-32
• /
• 1993

Recent studies have shown that a GABAergic mechanism in the brain modulates arterial blood pressure (BP) through alterations of sympathetic activity in the brain. The purpose of the present study was to determine if this modulation is involved in the pressor response to raised intracranial pressure (ICP). The pressor response to raised ICP was abolished by pretreatment of anesthetized rabbits with intracerebroventricular (icv) muscimol (a GABA agonist) as well as with icv clonidine $(an\;{\alpha}_2-agonist)$. Raising ICP in the hypertensive state after icv yohimbine $(an\;{\alpha}_2-antagonist)$ did not cause an additional increase in the BP, whereas raising ICP in the hypertensive state following icv bicuculline (a GABA antagonist) produced a further increase. Bicuculline produced an increase of the BP which had been lowered by muscimol or by clonidine, whereas it failed to increase the hypertensive state induced by either previous yohimbine or raised ICP. Yohimbine reversed the BP which had been made low by clonidine but was incapable of raising the hypotensive state after muscimol. Yohimbine failed to increase the heightened BP due to raised ICP, whereas bicuculline-induced pressor state was further elevated by yohimbine. Muscimol, besides the bicuculline-antagonizing property, inhibited the pressor response to yohimbine, suggesting participation of a GABAergic mechanism in the pressor action of yohimbine. From these results it was inferred that there were three ways in which BP could be increased via raised ICP: inactivation of the inhibitory sympathetic activity through (1) ${\alpha}_{2}-adrenoceptors$, (2) bicuculline-sensitive GABA receptors, (3) yohimbine-sensitive, clonidine-acting GABAergic sites.

• Journal of Yeungnam Medical Science
• /
• v.9 no.2
• /
• pp.359-381
• /
• 1992

This study was designed to investigate the effect of diazepam on the spontaneous contraction and oxytocin induced contraction of the isolated rat uterus. Female rat(Sprague-Dawley) pretreated with oophorectomy and 4 days administration of estrogen, weighing about 200 g, was sacrificed by cervical dislocation, and the uteruses were isolated. A longitudinal muscle strip was placed in temperature controlled($37^{\circ}C$) muscle chamber containing Locke's solution and myographied isometrically. Diazepam inhibited the spontaneous contraction and oxytocin induced contraction of the isolated rat uterus in a concentration-dependent manner. GABA, muscimol, a GABA A receptor agonist, bicuculline, a competitive GAGA A receptor antagonist, picrotoxin, a non competitive GABA A receptor antagonist, baclofen, a GABA B receptor agonist, and delta-aminovaleric acid, a GABA B receptor antagonist, did not affect on the spontaneous and oxytocin induced contraction of the isolated rat uterus. The inhibitory actions of diazepam on the spontaneous and oxytocin induced contraction were not affected by all the GABA receptor agonists and antagonists, but exceptionally potentiated by bicuculline. This potentiation-effect by bicuculline was not antagonized by muscimol. In normal calcium PSS, addition of calcium restored the spontaneous contraction preinhibited by diazepam and recovered the contractile of oxytocin preinhibited by diazepam. A23187, a calcium inophore, enhanced the restoration of both the spontaneous and oxytocin induced contraction by addition of calcium. In calcium-free PSS, diazepam suppressed the restoration of spontaneous motility by addition of calcium but allowed the recovery of spontaneous motility to a considerable extent. Diazepam could not inhibit some development of contractility by oxytocin in calcium-free PSS, but inhibited the increase in contractility by subsequent addition of calcium. These results suggest that the inhibitory action of diazepam on the rat uterine motility does not depend on or related to GABA receptors and that diazepam inhibits the extracellular calcium influx to suppress the spontaneous and oxytocin induced contractilities.