• Journal of Life Science
• /
• v.31 no.7
• /
• pp.662-670
• /
• 2021

Interstitial cells of Cajal (ICCs) are the pacemaking cells in the gastrointestinal (GI) muscles that generate the rhythmic oscillation in membrane potentials known as slow waves. In the present study, we investigated the effects of mirtazapine, a noradrenergic and serotonergic antidepressant, on pacemaking potential in cultured ICCs from the murine small intestine. The whole-cell patch-clamp configuration was used to record pacemaker potential in cultured ICCs. Mirtazapine induced pacemaker potential depolarizations in a concentration-dependent manner in the current clamp mode. Y25130 (a 5-HT3 receptor antagonist), RS39604 (a 5-HT4 receptor antagonist), and SB269970 (a 5-HT7 receptor antagonist) had no effects on mirtazapine-induced pacemaker potential depolarizations. Also, methoctramine, a muscarinic M₂ receptor antagonist, had no effect on mirtazapine-induced pacemaker potential depolarizations, whereas 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), a muscarinic M₃ receptor antagonist, inhibited the depolarizations. When guanosine 5'-[β-thio] diphosphate (GDP-β-S; 1 mM) was in the pipette solution, mirtazapine-induced pacemaker potential depolarization was blocked. When an external Ca²⁺ free solution or thapsigargin, a Ca²⁺-ATPase inhibitor of the endoplasmic reticulum, was applied, the generation of pacemaker potentials disappeared, and under these conditions, mirtazapine induced pacemaker potential depolarizations. In addition, protein kinase C (PKC) inhibitor, calphostin C, and chelerythrine inhibited mirtazapine-induced pacemaker potential depolarizations. These results suggest that mirtazapine regulates pacemaker potentials through muscarinic M₃ receptor activation via a G protein-dependent and an external or internal Ca²⁺-independent PKC pathway in the ICCs. Therefore, mirtazapine can control GI motility through ICCs.

• The Korean Journal of Physiology and Pharmacology
• /
• v.18 no.2
• /
• pp.149-153
• /
• 2014

Nausea and emesis are a major side effect and obstacle for chemotherapy in cancer patients. Employ of antiemetic drugs help to suppress chemotherapy-induced emesis in some patients but not all patients. Ginger, an herbal medicine, has been traditionally used to treat various kinds of diseases including gastrointestinal symptoms. Ginger is effective in alleviating nausea and emesis, particularly, for cytotoxic chemotherapy drug-induced emesis. Ginger-mediated antiemetic effect has been attributed to its pungent constituents-mediated inhibition of serotonin (5-HT) receptor activity but its cellular mechanism of action is still unclear. Emetogenic chemotherapy drugs increase 5-HT concentration and activate visceral vagal afferent nerve activity. Thus, 5-HT mediated vagal afferent activation is essential to provoke emesis during chemotherapy. In this experiment, water extract of ginger and its three major pungent constituent's effect on 5-HT-evoked responses were tested on acutely dispersed visceral afferent neurons with patch-clamp methods. The ginger extract has similar effects to antiemetic drug ondansetron by blocking 5-HT-evoked responses. Pungent constituents of the ginger, [6]-shogaol, [6]-gingerol, and zingerone inhibited 5-HT responses in a dose dependent manner. The order of inhibitory potency for these compounds were [6]-shogaol>[6]-gingerol>zingerone. Unlike well-known competitive 5-HT3 receptor antagonist ondansetron, all tested ginger constituents acted as non-competitive antagonist. Our results imply that ginger and its pungent constituents exert antiemetic effects by blocking 5-HT-induced emetic signal transmission in vagal afferent neurons.

• The Korean Journal of Pain
• /
• v.26 no.2
• /
• pp.125-129
• /
• 2013

Background: 5-hydroxytryptamine 3 (5-HT3) receptors have been known to be associated with the modulation of nociceptive transmission. However, it is uncertain whether 5-HT3 plays a role in the antinociceptive or pronociceptive pathway for incisional pain. In this study, we evaluated the effects of palonosetron, a 5-HT3 receptor antagonist, on incisional pain in rats when administered intrathecally or intraplantarly. Methods: An intrathecal catheter was implanted through the cisterna magna and placed in the intrathecal space of rats. An incision in the plantaris muscle of the right hind paw was done under anesthesia with sevoflurane. Withdrawal thresholds were evaluated with the von Frey filament after 2 hours. Palonosetron (0.5 and 0.1 ${\mu}g$ intrathecally; 0.5 ${\mu}g$ intraplantarly) was administered and the thresholds were observed for 4 hours. Results: Mechanical hypersensitivity developed after the incision. Intrathecal palonosetron (0.5 ${\mu}g$ and 0.1 ${\mu}g$) did not alter the paw withdrawal threshold. Intraplantar palonosetron (0.5 ${\mu}g$) also did not change the paw withdrawal threshold. Conclusions: Intrathecal and intraplantar palonosetron (0.5 ${\mu}g$) had no effect on modulating the mechanical hypersensitivity in the incisional pain model of rats.

• YAKHAK HOEJI
• /
• v.35 no.4
• /
• pp.326-331
• /
• 1991

Brain serotonin and its utilization was investigated on stressed rats after feeding high tryptophan diet for a month. High tryptophan fed rats displayed significantly higher level of serum tryptophan, brain tryptophan, serotonin (5-hydroxytryptamine; 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) than the control diet fed rats. When rats were treated with 3 hour immobilization (IMMB) stress, serotonin turnover was slightly increased, but not statistically significant, in control diet group rats. However in high tryptophan diet rats, 3 hr IMMB stress resulted in statistically significantly (p<0.05) decreased the serum tryptophan, brain tryptophan and 5-HT level. The concentration of 5-HIAA was significantly increased indicating accelerated utilization of the brain 5-HT of the high trp. fed rat. The utilization pattern of the serotonin was found to be similar among young and adult rats. Rats on a tryptophan enriched diet displayed higher coping ability to the stress as they exhibited smaller increment of corticosterone level. A possble involvement of opioid system was suggested in serotonin utilization by measuring total $^{3}$[H]-naloxone binding in brain.

• Korean Journal of Biological Psychiatry
• /
• v.4 no.1
• /
• pp.132-135
• /
• 1997

Current treatment strategies for levodopa-induced psychosis in advanced Parkinson's disease have had limited success. Reduction or discontinuation of levodopa and coadministration with dopamine-blocking neuroleptics may attenuate the psychotic symptoms, but these strategies are associated with worsening of parkinsonian symptoms. Administration of 5-HT3 receptor antagonist ; ondansetron, a newer strategy to attenuate psychosis of Parkinson'disease without motor deterioration was introduced. A 41-year-old young-onset male, who was diagnosed as Parkinson's disease 7 years ago, was treated with levodopa therapy, and had levodopa-induced psychosis(delusion, hallucination, paranoid, insomnia). After trial of ondansetron, he showed improvement in the Brief Psychiatric Rating Scale(from 21 points to 9 points) in spite of increasing the dosage of levodopa. With ondansetron, we could increase the dosage of levodopa without psychotic complications(esp, hallucination), and he showed improvement in the motor fluctuation.

• Bulletin of the Korean Chemical Society
• /
• v.29 no.1
• /
• pp.111-116
• /
• 2008

A piperazinylalkylisoxazole library containing 86 compounds was constructed and evaluated for the binding affinities to dopamine (D3) and serotonin (5-HT2A/2C) receptor to develop antipsychotics. Dopamine antagonists (DA) showing selectivity for D3 receptor over the D2 receptor, serotonin antagonists (SA), and serotonin-dopamine dual antagonists (SDA) were identified based on their binding affinity and selectivity. The analogues were divided into three groups of 7 DAs (D3), 33 SAs (5-HT2A/2C), and 46 SDAs (D3 and 5-HT2A/2C). A classification model was generated for identifying structural characteristics of those antagonists with different affinity profiles. On the basis of the results from our previous study, we conducted the generation of the decision trees by the recursive-partitioning (RP) method using Cerius2 2D descriptors, and identified and interpreted the descriptors that discriminate in-house antipsychotic compounds.

• The Korean Journal of Pharmacology
• /
• v.31 no.2
• /
• pp.141-144
• /
• 1995

Serotonergic neurons in brainstem play important roles in the endogenous descending pain inhibitory system. To illucidate the involvement of glutamate receptors in the regulation of brainstem serotonergic neurons, we studied the effects of glutamate receptor agonists on 5-hydroxytryptamine(5-HT) release from cultured neurons of rat fetal (gestational age 14th day) brainstem. Cultured cells maintained for 10 days in vitro were stimulated for 30 minutes with agonists of glutamate receptor subtypes at 10-1,000 micromolar concentration. Glutamate (10-1,000 M) increased 5-HT release in a concentration-dependent manner. N-methyl-D-aspartic acid $(NMDA)(10-1,000\;{\mu}M)$ increased 5-HT release in a concentration-dependent manner. Non-NMDA receptor agonists, kainate and $AMPA(3-1,000\;{\mu}M)$ also concentration-dependently increased 5-HT release. These results suggest that both NMDA and non-NMDA receptors regulate 5-HT release from brainstem serotonergic neurons.

• Journal of the Korean Society of Food Science and Nutrition
• /
• v.32 no.3
• /
• pp.437-443
• /
• 2003

Epidemiological data suggest that lycopene has anticancer activities in humans. Insulin-like growth factor-I receptor (IGF-IR) is a transmembrane tyrosine kinase that mediates the biological actions of IGFs and may play an active role in cancer progression. Because our previous in vitro studies have indicated lycopene inhibits HT-29 cell growth, the aim of this study was to determine whether lycopene induces apoptotic cell death and the inhibitory effect of lycopene on HT-29 cell growth is related to changes in IGF-IR levels and the receptor's intracellular signalling pathways. HT-29 cells were incubated for 4 days in serum-free medium in the presence of 0, 25, 50, or 100 $\mu$M lycopene, and the DNA fragmentation assay was performed. Cells treated with lycopene produced a distinct oligonucleosomal ladder with different sizes of DNA fragments, a typical characteristic of cells undergoing apoptosis. HT-29 cells were cultured for 4 days in serum-free medium in the presence of 0~100 $\mu$M lycopene and IGF-I (10nM) was added for 0~60 minutes immediately prior to lysate preparations. Western blot analysis of total lysates revealed that lycopene decreased the levels of IRS-1, Akt, phosphatidylinositol 3-kinase (PI3K), and IGF-IR $\beta$-subunit, and increased the levels of the IGF-IR precursor dose dependently. Lycopene also decreased IGF-I-induced phosphorylation of IGF-IR$\beta$, IRS-1 and Akt, which were, at least in part, due to decreased expression of these proteins. These results suggest that lycopene induces apoptosis of HT-29 cells by inhibiting IGF-IR signaling thereby interfering with an IGF-II-driven autocrine growth loop, which is known to exist in this cell line.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 1998.11a
• /
• pp.170-170
• /
• 1998

In order to discover new types of 5-hydroxytryptamine antagonists, we have devoted our attention to investigating naturally occurring compounds having anti-5HT activity in vitro. Recently, ${\gamma}$-mangostin [1,3,6,7-tetrahydroxy-2,8-bis(3-methyl-2-bytenyl)-9H-xanthen-9-one] from the fruit hull of Garcinia mangostana Linn has been shown to be a selective antagonist for 5-hydroxytryptamine$_{2A}$ receptors in smooth muscle and platelets. It is of interesting that y-mangostin which does not have a nitrogen atom, possesses marked 5-$HT_{2A}$ receptor blocking activity. The present study was undertaken to investigate the effects of ${\gamma}$-mangostin on central 5-HT receptors by using animal behavioural models. Intracerebronventricular injection of ${\gamma}$-mangostin (10-40n mol/mouse) inhibited 5-fluoro-${\alpha}$-methyltryptamin (5-FMT) (45 mg kg$^{-1}$, i.p.)-induced head-twitch response in mice in the presence or absence of citalopram (5-HT-uptake inhibitor). Neither the 5-FMT- nor the 8-hydroxy-2-( di-n-propylamino )tetralin (5-HT$_{1A}$-agonist)-induced 5-HT syndrome (head weaving and hindlimb abduction) was affected by ${\gamma}$-mangostin. The locomotor activity stimulated by 5-FMT through the activation of at-adrenoceptors did not alter in the presence of ${\gamma}$-mangostin. 5-HT-induced inositol phosphates accumulation in mouse brain slices was abolished by ketanserin. ${\gamma}$-Mangostin caused a concentration-dependent inhibition of the inositol phosphates accumulation and the binding of [$^3H$]-spiperone, a specific 5-$HT_{2A}$ receptor antagonist, to mouse brain membranes. Kinetic analysis of the [$^H3$]-spiperone binding revealed that ${\gamma}$-mangostin increased the $_{d}$ value without affecting the $B_{max}$ value, indicating the mode of the competitive nature of the inhibition by ${\gamma}$-mangostin. These results suggest that ${\gamma}$-mangostin inhibits 5-FMT-induced head-twitch response in mice by blocking 5-$HT_{2A}$ receptors not by blocking the release of 5-HT from the central neurone. ${\gamma}$-Mangostin is a promising 5-$HT_{2A}$ receptors antagonist in the central nervous system.m.

• Korean Journal of Veterinary Research
• /
• v.34 no.3
• /
• pp.447-456
• /
• 1994

In order to elucidate the characterization of receptors involved in inestinal motility of Israeli carp, spontaneously contracting Israeli carp intestinal preperations were prepared and mounted in the organ chambers for contraction traicings using a polygraph. Various contractile agonists were treated and their dose-response curves were constructed. $EC_{50}$ values$(pD_2)$ of each agonist on specific receptors, $pA_2$ values of competitive antagonists against some agonists, and $K_1$, values of noncompetitive antagonists against some agonists were analyzed for characterization of receptors related with the intestinal contraction. Results obtained through the experiments were summarized as follows: 1. Acetylcholine(ACh) exhibited biphasic dose-response curves: initial ACh-induced dose dependent contractions were observed in pM levels but followed by decreased response in in-between concentration levels. Dose dependent contractions reappeared in ${\mu}M$ level. The peaks in pM and ${\mu}M$ levels appeared in $10^{-13}M$ and $3{\times}10^{-5}M$, respectvely. 2. Carbachol(CaCh) exhibited dose dependent contractions from $10^{-9}M$ to $10^{-5}M$, and its $pD_2$ values were higher than those of ACh($5.60{\pm}0.11$). ACh and CaCh exhibited equiactive contractions. Nicotine had no effects on contractile responses of Israeli carp intestine. 3. ACh-induced responses were inhibited by atropine($K_1:7{\times}10^{-8}M$), a muscarinic antagonist, in a non-competitive manner. But CaCh-induced responses were inhibited by both antimuscarinic atropine($pA_2:9.52{\pm}0.14$) and selective $M_2$ antagonistic 4-DAMP($pA_2:8.16{\pm}0.09$), in competitive manners. Nicotine receptor antagonistic decamethonium and hexamethonium had no effects on ACh-and CaCh-induced contractions. Therefore, the cholinergic receptor related to intestinal motility of Israeli carp was assumed as $M_2$ type. 4. In Israeli carp intestine, 5-HT (serotonin) exhibited dose dependent contractions in concentration range from $10^{-8}M$ to $10^{-5}M$. The maximal responses, however, were corresponded to about 50% of those of ACh or CaCh. 5-HT induced contractions were inhibited by $5-HT_2$ antagonistic ketanserin ($K_1: 7.8{\times}10^{-4}M$) in a non-competitive manner, but not by both of anti $5-HT_1$, spiperone and anti $5-HT_3$, MDL-72222. Hence, $5-HT_2$ receptors are suggested to be existed in Isreli carp intestine.