• International Journal of Oral Biology
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• 제40권3호
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• pp.117-125
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• 2015

The present study investigated the role of central $GABA_A$ and $GABA_B$ receptors in orofacial pain in rats. Experiments were conducted on Sprague-Dawley rats weighing between 230 and 280 g. Intracisternal catheterization was performed for intracisternal injection, under ketamine anesthesia. Complete Freund's Adjuvant (CFA)-induced thermal hyperalgesia and inferior alveolar nerve injury-induced mechanical allodynia were employed as orofacial pain models. Intracisternal administration of bicuculline, a $GABA_A$ receptor antagonist, produced mechanical allodynia in naive rats, but not thermal hyperalgesia. However, CGP35348, a $GABA_B$ receptor antagonist, did not show any pain behavior in naive rats. Intracisternal administration of muscimol, a $GABA_A$ receptor agonist, attenuated the thermal hyperalgesia and mechanical allodynia in rats with CFA treatment and inferior alveolar nerve injury, respectively. On the contrary, intracisternal administration of bicuculline also attenuated the mechanical allodynia in rats with inferior alveolar nerve injury. Intracisternal administration of baclofen, a $GABA_B$ receptor agonist, attenuated the thermal hyperalgesia and mechanical allodynia in rats with CFA treatment and inferior alveolar nerve injury, respectively. In contrast to $GABA_A$ receptor antagonist, intracisternal administration of CGP35348 did not affect either the thermal hyperalgesia or mechanical allodynia. Our current findings suggest that the $GABA_A$ receptor, but not the $GABA_B$ receptor, participates in pain processing under normal conditions. Intracisternal administration of $GABA_A$ receptor antagonist, but not $GABA_B$ receptor antagonist, produces paradoxical antinociception under pain conditions. These results suggest that central GABA has differential roles in the processing of orofacial pain, and the blockade of $GABA_A$ receptor provides new therapeutic targets for the treatment of chronic pain.

• 대한의생명과학회지
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• 제14권2호
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• pp.69-76
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• 2008

${\gamma}$-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system, and its actions are mediated by subtypes of GABA receptors named as $GABA_A$, $GABA_B,\;and\;GABA_C,\;GABA_A$, receptor consisting of ${\alpha},\;{\beta},\;{\gamma}\;and\;{\delta}$ subunits is a heterooligomeric ligand-gated chloride channel. This study was performed to investigate regulation of $GABA_A$ receptor by protein kinase C(PKC). Ion currents were recorded using gramicidine-perforated patch and whole cell patch clamp. mRNA encoding the subunits of PKC expressed in major pelvic ganglion (MPG) neurons was detected by using RT-PCR. The GABA-induced inward current was increased by PKC activators and decreased by PKC inhibitors, respectively. These effects were not associated with intracellular $Ca^{2+}$ and GAG (1-oleoyl-2-acetyl-sn-glycerol), a membrane permeable diacylglycerol (DAG) analogue. These results mean that the subfamily of PKC participating in activation of $GABA_A$ receptor would be an atypical PKC (aPKC). Among theses, ${\xi}$ isoform of aPKC was detected by RT-PCR. Taking together, we suggest that excitable $GABA_A$ receptor in sympathetic MPG neuron seemed to be regulated by aPKC, particular in ${\xi}$ isoform. The regulatory roles of PKC on excitatory $GABA_A$ receptors in sympathetic neurons of MPG may be an important factor to control the functional activity of various pelvic organs such as bowel movement, micturition and erection.

• Biomolecules & Therapeutics
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• 제16권3호
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• pp.261-269
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• 2008

This experiment was performed to investigate the anxiolytic-like effects of cyclopeptide fraction alkaloids of Zizyphi Spinosi Semen (CFAZ), by using the experimental paradigms of anxiety, and compared with those of a known anxiolytic, diazepam. CFAZ (8.0 mg/kg, p.o.) increased the percentage of time spent on the open arms and the number of open arms entries in the elevated plus-maze test, increased the number of head dips in the hole-board test, and increased the percentage of center zone ambulatory time in the open-field box. However, CFAZ has no effect on the locomotor activity, while diazepam (2.0 mg/kg, p.o.) significantly reduced locomotor activity. CFAZ did not influence the grip force in the grip strength meter test, either. From the molecular experiments, CFAZ increased chloride influx in cultured cerebellar granule cells. In addition, $GABA_A$ receptors $\gamma$-subunit were over-expressed by CFAZ in cultured cerebellar granule cells. It is concluded that CFAZ may have anxiolytic-like effects, and these effects may be mediated by $GABA_A$ receptors.

• 대한불안의학회지
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• 제2권2호
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• pp.79-85
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• 2006

Anxiety and anxiety disorders are related to many neurotransmitters, such as norepinephrine, serotonine, dopamine, glutamate, and Gamma-aminobutyric acid (GABA). GABA, the main inhibitory neurotransmitter of the CNS, is known to counterbalance the action of the excitatory neurotransmitters and control anxiety. GABA acts on 3 GABA receptor subtypes, $GABA_A$, $GABA_B$, and $GABA_C$. $GABA_A$ and $GABA_c$ receptors are oligomeric transmembrane glycoproteins composed of 5 subunits that are arranged around a central chloride channel. $GABA_B$ receptor comprises two 7-transmembraneis-spanning proteins that are coupled to either calcium or potassium channel via G proteins. This article highlights neurobiological interactions between anxiety and GABA system.

• 한국작물학회지
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• 제57권2호
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• pp.144-150
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• 2012

${\gamma}$-Aminobutyric acid (GABA) is a non-protein amino acid that is widely distributed in plant and animal kingdom. GABA is found in tissues of the central nervous system (CNS) in animals. GABA functions as a the major inhibitory neurotransmitter in the CNS by acting through the GABA receptors. Clinical studies have revealed the relationship between an increased intake of GABA or analogues with several health benefits, including lowering of blood pressure in mildly hypertensive animals and humans. Furthermore, GABA would also has an inhibitory effect on cancer cell proliferation, stimulates cancer cell apoptosis and plays a role in alcohol-associated diseases and schizophrenia. In plants, interest in the GABA emerged mainly from experimental observations that GABA is largely and rapidly produced in large amounts in response to biotic and abiotic stresses. In this study, we speculated the properties and metabolism of GABA in plant and functions in relation to the responses to environmental stresses.

• The Korean Journal of Pain
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• 제20권2호
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• pp.106-110
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• 2007

Background: A phosphodiesterase 5 inhibitor, sildenafil, has been effective against nociception. Several lines of evidence have demonstrated the role of the GABAergic pathway in the modulation of nociception. The impact of the GABA receptors on sildenafil was studied using the formalin test at the spinal level. Methods: Male SD rats were prepared for intrathecal catheterization. The formalin test was induced by subcutaneous injection of formalin solution. The change in the activity of sildenafil was examined after pre-treatment with GABA receptor antagonists ($GABA_A$ receptor antagonist, bicuculline; $GABA_B$ receptor antagonist, saclofen). Results: Intrathecal sildenafil dose-dependently attenuated the flinching observed during phase 1 and 2 in the formalin test. The antinociceptive effect of sildenafil was reversed by the $GABA_B$ receptor antagonist (saclofen) but not by the $GABA_A$ receptor antagonist (bicuculline) in both phases. Conclusions: Intrathecal sildenafil suppressed acute pain and the facilitated pain state. The antinociception of sildenafil is mediated via the $GABA_B$ receptor, but not the $GABA_A$ receptor, at the spinal level.

• The Korean Journal of Pain
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• 제36권4호
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• pp.441-449
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• 2023

Background: Hypertonic saline is used for treating chronic pain; however, clinical studies that aid in optimizing therapeutic protocols are lacking. We aimed to determine the concentration of intrathecally injected hypertonic saline at which the effect reaches its peak as well as the underlying γ-aminobutyric acid (GABA) receptor-related antinociceptive mechanism. Methods: Spinal nerve ligation (SNL; left L5 and L6) was performed to induce neuropathic pain in rats weighing 250-300 g. Experiment 1: one week after implanting the intrathecal catheter, 60 rats were assigned randomly to intrathecal injection with 0.45%, 0.9%, 2.5%, 5%, 10%, and 20% NaCl, followed by behavioral testing at baseline and after 30 minutes, 2 hours, 1 day, and 1 week to determine the minimal concentration which produced maximal analgesia. Experiment 2: after determining the optimal intrathecal hypertonic saline concentration, 60 rats were randomly divided into four groups: Sham, hypertonic saline without pretreatment, and hypertonic saline after pretreatment with one of two GABA receptor antagonists (GABA_A [bicuculline], or GABA_B [phaclofen]). Behavioral tests were performed at weeks 1 and 3 following each treatment. Results: Hypertonic saline at concentrations greater than 5% alleviated SNL-induced mechanical allodynia and had a significant therapeutic effect, while showing a partial time- and dose-dependent antinociceptive effect on thermal and cold hyperalgesia. However, pretreatment with GABA receptor antagonists inhibited the antinociceptive effect of 5% NaCl. Conclusions: This study indicates that the optimal concentration of hypertonic saline for controlling mechanical allodynia in neuropathic pain is 5%, and that its analgesic effect is related to GABA_A and GABA_B receptors.

• Natural Product Sciences
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• 제23권1호
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• pp.53-60
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• 2017

Perillae Herba has been traditionally used for the sedation in the oriental countries. Therefore, this study was conducted to determine whether Perillae Herba ethanol extract (PHEE) enhances pentobarbital-induced sleeping behaviors in animals. In addition, the possible mechanisms are demonstrated. PHEE (12.5, 25 and 50 mg/kg. p.o.) reduced the locomotor activity in mice. PHEE reduced sleep latency and augmented the total sleep time in pentobarbital (42 mg/kg, i.p.)-induced sleep in mice. Furthermore, the number of sleeping mice treated with sub-hypnotic pentobarbital (28 mg/kg, i.p.) increased. PHEE (50 mg/kg. p.o.) decreased the sleep/wake cycles and wakefulness, and increased total sleeping time and NREM sleep in electroencephalogram (EEG) of rats. In addition, PHEE (0.1, 1.0 and $10{\mu}g/ml$) increased the intracellular $Cl^-$ level through the GABA receptors in the hypothalamus of rats. Moreover, the protein of glutamate decarboxylase (GAD) was overexpressed by PFEE. It was found that PHEE enhanced pentobarbital-induced sleeping behaviors through $GABA_A-ergic$ transmissions.

• The Korean Journal of Physiology and Pharmacology
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• 제5권2호
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• pp.189-197
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• 2001

To investigate propofol's effects on ionic currents induced by ${\gamma}-aminobutyric$ acid (GABA) and glycine as well as on those produced by the nicotinic acetylcholine- and glutamate-responsive channels, rat dorsal raphe neurons were acutely dissociated and the nystatin-perforated patch-clamp technique under voltage-clamp conditions was used to observe their responses to the administration of propofol. Propofol evoked ion currents in a dose-dependent manner, and propofol $(10^{-4}\;M)$ was used to elicit ion currents through the activation of $GABA_A,$ glycine, nicotinic acetylcholine and glutamate receptors. Propofol at a clinically relevant concentration $(10^{-5}\;M)$ potentiated $GABA_A-,$ glycine- and NMDA receptor-mediated currents. The potentiating action of propofol on $GABA_A-,$ glycine- and NMDA receptor-mediated responses involved neither opioid receptors nor G-proteins. Apparently, propofol modulates inhibitory and excitatory neurotransmitter-activated ion channels either by acting directly on the receptors or by potentiating the effects of the neurotransmitters, and this modulation appears to be responsible for the majority of the anaesthetic and/or adverse effects.

• The Korean Journal of Pain
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• 제28권1호
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• pp.4-10
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• 2015

Etifoxine (etafenoxine, $Stresam^{(R)}$) is a non-benzodiazepine anxiolytic with an anticonvulsant effect. It was developed in the 1960s for anxiety disorders and is currently being studied for its ability to promote peripheral nerve healing and to treat chemotherapy-induced pain. In addition to being mediated by $GABA_A{\alpha}2$ receptors like benzodiazepines, etifoxine appears to produce anxiolytic effects directly by binding to ${\beta}2$ or ${\beta}3$ subunits of the $GABA_A$ receptor complex. It also modulates $GABA_A$ receptors indirectly via stimulation of neurosteroid production after etifoxine binds to the 18 kDa translocator protein (TSPO) of the outer mitochondrial membrane in the central and peripheral nervous systems, previously known as the peripheral benzodiazepine receptor (PBR). Therefore, the effects of etifoxine are not completely reversed by the benzodiazepine antagonist flumazenil. Etifoxine is used for various emotional and bodily reactions followed by anxiety. It is contraindicated in situations such as shock, severely impaired liver or kidney function, and severe respiratory failure. The average dosage is 150 mg per day for no more than 12 weeks. The most common adverse effect is drowsiness at the initial stage. It does not usually cause any withdrawal syndromes. In conclusion, etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired psychomotor performance, and withdrawal syndromes than those of benzodiazepines. It potentiates $GABA_A$ receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of TSPO. It seems promising that non-benzodiazepine anxiolytics including etifoxine will replenish shortcomings of benzodiazepines and selective serotonin reuptake inhibitors according to animated studies related to TSPO.