The Japanese Journal of Pharmacology
Online ISSN : 1347-3506
Print ISSN : 0021-5198
ISSN-L : 0021-5198
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Volume 76, Issue 3
Displaying 1-12 of 12 articles from this issue
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Review
  • Evidence for the Existence of the β-Endorphin-Sensitive “ε-Opioid Receptor” in the Brain: The Mechanisms of ε-Mediated Antinociception
    Minoru Narita, Leon F. Tseng
    1998 Volume 76 Issue 3 Pages 233-253
    Published: 1998
    Released on J-STAGE: April 26, 2001
    DOIhttps://doi.org/10.1254/jjp.76.233
    JOURNAL FREE ACCESS
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    Recently, μ-, δ- and κ-opioid receptors have been cloned and relatively well-characterized. In addition to three major opioid receptor types, more extensive studies have suggested the possible existence of other opioid receptor types that can be classified as non-μ, non-δ and non-κ. Based upon anatomical and binding studies in the brain, the sensitive site for an endogenous opioid peptide, β-endorphin, has been postulated to account for the unique characteristics of the opioid receptor defined as a putative ε-opioid receptor. Many ε-opioid receptors are functionally coupled to G-proteins. The functional ε-opioid receptors in the brain are stimulated by bremazocine and etorphine as well as β-endorphin, but not by selective μ-, δ- or κ-opioid receptor agonists. ε-Opioid receptor agonists injected into the brain produce profound antinociception. The brain sites most sensitive to ε-agonist-induced antinociception are located in the caudal medial medulla such as the nucleus raphe obscures, nucleus raphe pallidus and the adjacent midline reticular formation. The stimulation of ε-opioid receptors in the brain facilitates the descending enkephalinergic pathway, which probably originates from the brainstem terminating at the spinal cord. The endogenous opioid Met-enkephalin, released in the spinal cord by activation of supraspinal ε-opioid receptors, stimulates spinal δ2-opioid receptors for the production of antinociception. It is noteworthy that the ε-opioid receptor-mediated pain control system is different from that of other opioid systems. Although there appears to be no ε-selective ligand currently available, these findings provide strong evidence for the existence of the putative ε-opioid receptor and its unique function in the brain.
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  • Pleckstrin Homology Domain as an Inositol Compound Binding Module
    Masato Hirata, Takashi Kanematsu, Hiroshi Takeuchi, Hitoshi Yagisawa
    1998 Volume 76 Issue 3 Pages 255-263
    Published: 1998
    Released on J-STAGE: April 26, 2001
    DOIhttps://doi.org/10.1254/jjp.76.255
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    Many of the proteins that participate in cell signalling contain structural modules involved in regulatory interactions between components of signal transduction cascades. One of such modules is the pleckstrin homology (PH) domain, a region of approximately 120 amino acids that can form an electrostatically polarized tertiary structure. Several molecules such as inositol 1, 4, 5-trisphosphate/phosphatidylinositol 4, 5-bisphosphate, the βγ-subunits of heterotrimeric G proteins and protein kinase C have been proposed as common ligands for the PH domain. Through these potential interactions, the PH domain has been proposed to play a role in membrane recruitment of proteins containing the PH domain, thus targeting them to appropriate cellular compartment or enabling them to interact with other components of the signal transduction pathway. In this review, we mainly focus on membrane targeting through the binding to inositol phosphates/phosphoinositides.
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Regular Papers
  • Effects of the Novel Tricyclic Quinoxalinedione Derivatives, SM-18400 and Its Analogs, on N-Methyl-D-aspartate (NMDA) Receptor-Mediated Synaptic Transmission in the Isolated Neonatal Rat Spinal Cord In Vitro
    Yoshimi Maruoka, Yukihiro Ohno, Hiroyasu Tanaka, Hirokazu Yasuda, Ken- ...
    1998 Volume 76 Issue 3 Pages 265-270
    Published: 1998
    Released on J-STAGE: April 26, 2001
    DOIhttps://doi.org/10.1254/jjp.76.265
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    We examined the effects of novel tricyclic quinoxalinedione derivatives, SM-18400 ((S)-9-chloro-5-[p-aminomethyl-o-(carboxymethoxy)phenylcarbamoylmethyl]-6, 7-dihydro-1H, 5H-pyrido[1, 2, 3-de]quinoxaline-2, 3-dione hydrochloride trihydrate) and its analogs (i.e., ID-17263 and ID-17332), on the N-methyl-D-aspartate (NMDA) receptor-mediated polysynaptic reflex (PSR) in the isolated spinal cord of neonatal rats in vitro. Application of SM-18400 selectively suppressed the PSR activity in a concentration-dependent manner without affecting the monosynaptic reflex (MSR). Differential suppression of the PSR was also obtained with ID-17263, ID-17332 and other known NMDA receptor glycine-binding site antagonists, 5, 7-dichlorokynurenate (5, 7-diClkyn) and L-689, 560 (4-trans-2-carboxy-5, 7-dichloro-4-phenylaminocarbonylamino-1, 2, 3, 4-tetrahydroquinoline). Relative potencies of the test drugs for inhibition of the PSR were as follows: SM-18400 >> L-689, 560 > ID-17332 > ID-17263 > 5, 7-diClkyn. In addition, the inhibitory effects of SM-18400 on PSR were markedly antagonized by simultaneous application of D-serine, an agonist for NMDA receptor glycine-binding sites. These findings suggest that SM-18400 is a potent NMDA receptor glycine-binding site antagonist and blocks the NMDA receptor-mediated synaptic neurotransmission in the spinal cord in vitro.
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  • Treatment With Bovine Gallstones Exacerbates Liver Damage, but Enhances Hepatoprotection by Bear Gall Powder in Carbon Tetrachloride-Intoxicated Rats
    Toshiaki Nakashima, Ninko Matsumoto, Kei Kashima
    1998 Volume 76 Issue 3 Pages 271-277
    Published: 1998
    Released on J-STAGE: April 26, 2001
    DOIhttps://doi.org/10.1254/jjp.76.271
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    The interactions between bovine gallstones (Goou) and bear gall powder (Yutan) in decreases in serum transaminase levels were investigated in rats intoxicated with carbon tetrachloride (CCl4). The p.o. administration of Goou significantly increased both serum transaminase levels and hepatic lipid peroxidation following i.p. administration of CCl4. Concomitant administration of both Goou and Yutan resulted in decreases of serum transaminase levels and hepatic lipid peroxidation, which were more remarkable than with administration of Yutan alone. Goou significantly increased the estimated hepatic blood flow in the indocyanine green clearance test and enhanced the delivery of CCl4 to the liver from the peritoneal cavity. These findings suggest that Goou exacerbates CCl4-induced hepatic damage because of the accelerated delivery of CCl4 to the liver and that Goou might have a hemodynamic drug interaction with Yutan in the liver, possibly enhancing the hepatoprotective effect of Yutan.
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  • Effects of Rabeprazole, a Gastric Proton Pump Inhibitor, on Biliary and Hepatic Lysosomal Enzymes in Rats
    Hideaki Fujisaki, Kiyoshi Oketani, Jun-ichi Nagakawa, Osamu Takenaka, ...
    1998 Volume 76 Issue 3 Pages 279-288
    Published: 1998
    Released on J-STAGE: April 26, 2001
    DOIhttps://doi.org/10.1254/jjp.76.279
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    The effects of rabeprazole (E3810), omeprazole and chloroquine on hepatic lysosomal function were studied. After chloroquine (50 mg/kg), rabeprazole (5 mg/kg) or omeprazole (5 mg/kg) was given intraperitoneally to rats for 6 days, the bile was collected via a bile duct cannula for 5 hr, and hepatic and biliary lysosomal enzyme (N-acetyl-β-glucosaminidase and β-galactosidase) activities were measured. The latency (an index for the hepatic lysosomal membrane integrity) was calculated from the N-acetyl-β-glucosaminidase activity. The biliary constituents and plasma concentrations of lipids were also measured. The administration of chloroquine significantly increased hepatic and biliary lysosomal enzyme activities, but did not affect the lysosomal enzyme latency, hepatic and biliary protein content or bile flow. It significantly decreased the bile acid level. On the other hand, the administration of rabeprazole and omeprazole did not alter the lysosomal enzyme activities, lysosomal enzyme latency, protein content in liver or liver weight. Furthermore, no significant differences were observed in biliary lysosomal enzyme activity, protein content, bile flow, biliary constituents or in the plasma concentrations of lipids between the drug groups (rabeprazole or omeprazole) and the control group. The results of the present study indicate that rabeprazole, like omeprazole, does not influence hepatic lysosomal function.
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  • Radioligand Binding Characteristics of the Endothelin Receptor in the Rabbit Iris
    Chihiro Nosaka, Hitoshi Ishikawa, Isao Haruno, Takeshi Yoshitomi, Hiro ...
    1998 Volume 76 Issue 3 Pages 289-296
    Published: 1998
    Released on J-STAGE: April 26, 2001
    DOIhttps://doi.org/10.1254/jjp.76.289
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    We previously suggested the presence of functionally atypical endothelin (ET) A receptors in the rabbit iris sphincter. Here, we further characterized the ET receptor by a radioligand-receptor binding study utilizing a membrane fraction of the rabbit iris. In addition, we functionally confirm the presence of an atypical ETA receptor in the iris dilator similar to that in the iris sphincter. In binding experiments, [125I]ET-1 was completely displaced by ET-3 in a biphasic fashion, but only partially by BQ-123 and ETB ligands. In the presence of RES-701, ET-3 and sarafotoxin (SRTX)-b completely displaced [125I]ET-1 in a monophasic fashion, but with shallow slopes. Moreover, ET-1, ET-3 and SRTX-b completely displaced [3H]BQ-123 with IC50 values of 0.8, 81 and 4.4 nM, respectively, but with slopes of ET-3 and SRTX-b being again shallow. In iris dilator muscles, ET-3 showed lower and SRTX-b showed higher contractile activities than ET-1. SRTX-c was inactive. BQ-123 more preferentially antagonized ET-3 and SRTX-b than ET-1, with the Schild plot slope of SRTX-b being shallow. Thus, functional experiments suggested the presence of atypical ETA receptors in the iris dilator similar to the iris sphincter. However, the binding experiments suggested the presence of rather typical ETA- and ETB-like receptors. Therefore, we apparently failed to show ET binding sites corresponding to functionally atypical ETA receptors.
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  • Effect of 5-｛3-[((2S)-1, 4-Benzodioxan-2-ylmethyl)amino]propoxy｝-1, 3-benzodioxole HCl (MKC-242), a Novel 5-HT1A-Receptor Agonist, on Aggressive Behavior and Marble Burying Behavior in Mice
    Michikazu Abe, Hiroshi Nakai, Reiko Tabata, Ken-Ichi Saito, Mitsuo Ega ...
    1998 Volume 76 Issue 3 Pages 297-304
    Published: 1998
    Released on J-STAGE: April 26, 2001
    DOIhttps://doi.org/10.1254/jjp.76.297
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    Behavioral effects of 5-｛3-[((2S)-1, 4-benzodioxan-2-ylmethyl)amino]propoxy｝-1, 3-benzodioxole HCl (MKC-242), a novel 5-HT1A-receptor agonist, were evaluated using animal models of anxiety and obsessive compulsive disorder and compared against reference compounds. MKC-242 suppressed foot shock-induced fighting behavior without loss of motor coordination in mice as the reference compounds did. The ED50 values of MKC-242, buspirone, tandospirone and diazepam were 1.7, 42, 80 and 2.0 mg/kg, p.o., respectively. The duration of the suppression of fighting by MKC-242 was longer than those of buspirone and tandospirone and comparable to that of diazepam. Similar results were also obtained with the water-lick conflict test in rats. The plasma concentration of MKC-242 in rats was much higher than the reported value of buspirone during 0.25 – 6 hr after oral administration. In addition, MKC-242 reduced marble burying behavior without reduction of motor activity. Fluoxetine, tandospirone and diazepam also reduced the behavior at non-sedative doses. These findings indicate that MKC-242 possesses a longer-lasting anxiolytic effect than azapirones. This might be due to the high concentration of the compound in plasma. In addition, it is also suggested that MKC-242 possesses an antiobsessional effect.
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Short Communications
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