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K Kisara

Publications and source records attributed to K Kisara.

At least 55 records · Page 3Linked to original sources
PubMed1998

Properties of specific binding site of myotoxin a, a powerful convulsant, in brain microsomes.

Myotoxin a, a small basic polypeptide from prairie rattlesnakes (Crotalus viridis viridis), induces myonecrosis and binds to a single class of binding sites in skeletal muscle sarcoplasmic reticulum. In the present study, [125I]myotoxin a with a high specific activity was prepared and it was shown to bind mainly to microsomes in rat whole brain. [125I]Myotoxin a was further shown to bind to microsomes prepared from all regions tested in brain. Its specific binding to whole brain microsomes was of approximately 1.9 times lower affinity (KD = 0.76 microM; Bmax = 13.1 nmol/mg) than that to skeletal muscle sarcoplasmic reticulum. [125I]Myotoxin a binding to brain microsomes was displaced by unlabeled myotoxin a with an IC50 value of 4.5 microM. [125I]Myotoxin a binding was markedly reduced by treatment of microsomes with trypsin, suggesting that the binding site of [125I]myotoxin a is partially proteins. The binding was significantly inhibited by Mg2+ at concentrations above 1 mM. Having looked at several drugs, we noted that [125I]myotoxin a binding was noncompetitively inhibited by spermine, whereas it was enhanced by heparin. On the other hand, the i.c.v. injection of myotoxin a in mice induced potent convulsive effects at 0.05 nmol/mouse or more. This paper is the first to show that the specific binding site of myotoxin a is present in mouse brain and that myotoxin a is a novel peptidic convulsant in mice.

Animals↗
PubMed1997

[Pharmacological profile of sendide, a tachykinin NK-1 receptor antagonist].

Progress in the characterization of tachykinin receptors and the understanding of the physiological and pathological roles of tachykinins is highly dependent on the discovery of potent and selective antagonists with metabolic stability. We have recently described a peptidic antagonist of the tachykinin NK-1 receptor, sendide (Tyr-D-Phe-Phe-D-His-Leu-Met-NH2), that is a selective and extremely potent antagonist of NK-1 receptors, but displays no antagonistic activity on the response induced by NK-2- or NK-3-receptor agonists in the mouse spinal cord. When co-administered with substance P (SP) intrathecally (i.t.), sendide markedly inhibited the scratching, biting and licking behavior induced by SP in a dose-dependent manner. The antagonistic effect of sendide on the SP-induced behavioral response was approximately 7300 times more potent than that of CP-96,345, a non-peptidic NK-1-receptor antagonist. The duration of the antagonistic effect of sendide was longer than that of CP-96,345. The behavioral response elicited by other NK-1-receptor agonists, septide, physalaemin and [Sar9, Met (O2)11]-SP, was reduced significantly by a small dose of sendide. In the [3H]-SP binding assay using mouse spinal cord membranes, sendide potently displaced [3H]-SP binding, with a potency approximately 5.4 x 10(4) times greater than that of CP-96,345. Moreover, i.t. administration of sendide was found to produce the antinociceptive effect through the blockage of NK-1 receptors in the mouse formalin and capsaicin tests. Sendide is therefore likely to become a powerful pharmacological tool for studying the functional roles of NK-1 receptors in the central nervous system.

Analgesics↗
PubMed1997

[Relationship between learning behavior and genetic factor on immobility shown during forced swimming test].

The relationship between learning and genetic factor on immobility in mice during a forced swimming test (FST) has been studied. The duration of immobility during the FST did not change significantly after the administration of either scopolamine (2.5 mg/kg, ip) or cyclohexamine (150 mg/kg, ip), although both drugs produced impairment in the learning task. This suggests that the increase in immobility observed during the second trial of the FST may not be related to learning which could occur during the first trial. Concerning the strain difference, first, the duration of immobility in C3H mice was shorter than that in ICR, ddY, C57BL and BALB mice. Second, after receiving shock stress in a box, ICR, ddY and C57BL mice, but not C3H mice showed a marked decrease in locomotor activity when placed in the box again without shock. Also during the FST, both C57BL and ddY mice, but not C3H mice showed prolongation of immobility and reduction in swimming after shock stress. The changes in locomotor activity, and immobility and swimming during the FST caused by shock stress in ddY mice recovered to normal levels after treatment with imipramine. From these results, it is suggested that the immobility shown during the FST, which may be independent of learning and dependent on some genetic factor, is a suitable model of depression in animals.

Animals↗
PubMed1997

Involvement of dopaminergic neurons in mouse-killing aggression in rats.

The sites associated with dopamine neurons which produce mouse-killing aggression (muricide) were examined in the rat brain. Muricide appeared in 60-80% of rats after being fed a thiamine-deficient diet for 28 days. Microinjection of dopamine (500 ng/rat) into the olfactory bulb (OB) significantly suppressed muricide, whereas injection into other brain areas failed to do so. The incidence of muricide after dopamine injection was 40% at 5 min and 20% at 15-30 min. When 6-hydroxydopamine (8 micrograms/0.5 microliter), following pretreatment with desmethylimipramine (25 mg/kg i.p.), was injected twice into the ventral tegmental area (VTA) or the olfactory bulb (OB) in nonkiller rats during thiamine-deficient feeding, the occurrence of muricide gradually increased over time. The present results suggest that degeneration of dopamine neurons projecting from the VTA to the OB may be related to mouse-killing aggression in rats.

Aggression↗
PubMed1996

Inhibition of dynorphin-converting enzymes prolongs the antinociceptive effect of intrathecally administered dynorphin in the mouse formalin test.

The effects of peptidase inhibitors on the antinociceptive induced by intrathecally (i.t.) administered by dynorphin A and dynorphin B in the mouse formalin test were examined. When administered i.t. 5 min before the injection of 0.5% formalin solution into the dorsal surface of a hindpaw, dynorphin A (0.5-2 nmol) and dynorphin B (2-8 nmol) produced a dose-dependent and significant reduction of the paw-licking response. Dynorphin A (2 nmol) and dynorphin B (8 nmol)-induced antinociception disappeared completely within 90 min and 60 min, respectively. p-Hydroxymercuribenzoate, a cysteine proteinase inhibitor, and phosphoramidon, and endopeptidase 24.11 inhibitor simultaneously administered with dynorphin A or dynorphin B. Significantly prolonged antinociception induced by both dynorphins. However, captopril, and angiotensin-converting enzyme inhibitor, bestatin (a general aminopeptidase inhibitor) and a serine proteinase inhibitor phenylmethanesulfonyl fluoride, were active. Dynorphin converting enzyme(s) transform dynorphin-related peptides to [Leu5]enkephalin and [Leu5]enkephalin-Arg6. Neither [Leu5]enkephalin nor [Leu5]enkephalin-Arg6, even at high dose (10 nmol), produced any antinociceptive effect. However, [Leu5[enkephalin-Arg6, but not [Leu5]enkephalin, produced a significant antinociceptive effect when co-administered with phosphoramidon. Therefore, the prolongation of the antinociception induced by both dynorphins in the presence of phosphoramidon, may be due to inhibition of [Leu5]enkephalin-Arg6 degradation. The present results indicate that dynorphin-converting enzyme(s) may be important enzyme(s) responsible for terminating dynorphin-A- and dynorphin-B-induced antinociception at the spinal cord level in mice.

Analgesia↗
PubMed1996

Spinally-mediated behavioural responses evoked by intrathecal high-dose morphine: possible involvement of substance P in the mouse spinal cord.

Intrathecal (i.t.) administration of morphine in the spinal subarachnoid space of mice produced a severe hindlimb scratching followed by biting and licking. The onset of the scratching behaviour was observed 60-70 s after i.t. injection of morphine (60 and 90 nmol), and had a duration of 3-4 min. The morphine-induced behaviour was increased additively by i.t. co-administration of substance P (SP). This characteristic behavioural response was inhibited dose-dependently by i.t. co-administration of the tachykinin NK-1 receptor antagonists, sendide and CP-96,345. Significant antagonistic effects of SP (1-7), a putative antagonist for NK-1 receptors and [D-Phe7, D-His9]SP (6-11), a selective antagonist for SP receptors, were observed against the morphine-induced behaviour. Pretreatment with i.t. SP antiserum and i.t. capsaicin resulted in reduction of the response to morphine. I.t. administration of somatostatin (SOM) antiserum, cysteamine, a relatively selective depletor of SOM and cyclo-SOM, a SOM receptor antagonist, produced no inhibitory effect on the morphine-induced behaviour. These results demonstrate that a spinal system of neurones containing SP may be involved in elicitation of the behavioural episode following i.t. injection of morphine in mice.

Animals↗
PubMed1996

Effect of spinal nitric oxide inhibition on capsaicin-induced nociceptive response.

Pretreatment with the nitric oxide synthase (NOS) inhibitor L-NG-nitro arginine methyl ester (L-NAME), injected intraperitoneally (i.p.) or intrathecally (i.t.), produced a significant antinociception in the mouse assessed by the capsaicin-induced paw licking procedure. Varying the administration time of an effective dose of L-NAME (160nmol, i.t.) resulted in a significant decrease of the brief nociceptive behavioral response induced by capsaicin, even when L-NAME was given 2 hr before capsaicin. L-NAME, injected i.p. or i.t., produced a dose-related reduction in paw licking in the second phase of the formalin (2.0%) response without affecting the first phase. L-Arginine (600 mg/kg, i.p.) but not D-arginine (600 mg/kg, i.p.) reversed the antinociceptive effect of L-NAME in the capsaicin test. Antinociceptive effect of L-NAME, injected i.p. or i.t., was more potent in the second phase response of formalin-induced paw licking than in capsaicin-induced nociceptive response. The inhibitory action of L-NAME was reversed by L-arginine but not D-arginine in the second phase response. L-Arginine alone was without affecting capsaicin- and formalin-induced nociceptive responses. These results suggest that spinal nitric oxide (NO) may be involved in the mechanisms of capsaicin-induced brief nociceptive stimuli, but not in the first, acute phase of the formalin-induced response in mice.

Animals↗
PubMed1996

Involvement of nitric oxide in spinally mediated capsaicin- and glutamate-induced behavioural responses in the mouse.

The intrathecal (i.t.) injection of capsaicin (0.1 nmol/mouse) through a lumbar puncture elicited scratching, biting and licking responses. Pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (320 nmol), by i.t. injection, resulted in a significant inhibition of the behavioural response produced by i.t. capsaicin (0.1 nmol/mouse). Similar behavioural responses were induced by i.t. injections of NMDA (0.4 nmol), kainate (0.05 nmol) or AMPA (0.05 nmol), which were all inhibited by co-administration of L-NAME (20-80 nmol). L-Arginine (600 mg/kg, i.p.) but not D-arginine (600 mg/kg, i.p.) reversed the inhibitory effect of L-NAME on capsaicin-, NMDA-, kainate- and AMPA-induced behavioural response. Scratching, biting and licking responses induced by tachykinin receptor agonists, substance P, [Sar9,Met(O2)11]substance P, neurokinin A and neurokinin B were not affected by co-administration of L-NAME (40 and 80 nmol). These results suggest that spinal nitric oxide may play a significant role in mechanisms of the behavioural response to capsaicin, probably through the release of glutamate, but not tachykinins.

Animals↗
PubMed1995

Immunohistochemical determination of rat spinal cord substance P, and antinociceptive effect during development of thiamine deficiency.

During 30 days of thiamine deficiency (TD) feeding, the rat antinociceptive effect (pain threshold) to noxious heat stimulation was significantly increased in proportion to the decrease substance P (SP) fluorescent intensity in the spinal cord. Only a single injection of thiamine HCl (0.5 mg/kg, s.c.) on the early treatment day during TD feeding effectively reversed the analgesic effect to the pair-fed control level. Whereas this reversal effect by thiamine treatment was not found if this treatment was done on the relatively late day. However, either treatment day, except muricide, complete disappearance of various animal behaviours induced by TD was found. These results indicate that, after certain degree of TD development, TD-induced behavioral effects might be reversible, but the afferent nerve fibers might be irreversibly damaged, probably by the similar mechanism as found for an excitotoxin(s) mediated injury in the certain brain region(s). The results also suggest a possibility that SP and an excitotoxin, glutamate, in the dorsal part of the spinal cord greatly contribute to the pain transmission induced by noxious heat stimulation.

Animals↗
PubMed1995

alpha-Methylated tryptamine derivatives induce a 5-HT receptor-mediated head-twitch response in mice.

The two alpha-methylated tryptamine derivatives, 5- (5-FMT) and 6-fluoro-alpha-methyltryptamine (6-FMT), rapidly induced a head-twitch response (HTR) in mice. Two derivatives that lack the methyl group in their chemical structures, 5- (5-FT) and 6-fluorotryptamine (6-FT), did not induce the HTR. The induced HTR was depressed by pretreatment with cycloheptadine, p-chlorophenylalanine or fluoxetine, but was potentiated by 5,7-dihydroxytryptamine. Both 5- and 6-FMT increased brain 5-HT levels in hypothalamus, hippocampus, brainstem, striatum and cortex. 5-FMT decreased the levels of 5-hydroxyindoleacetic acid in those regions, but 6-FMT caused a significant decrease in only the hypothalamus and cortex. The two methylated derivatives inhibited mouse brain MAO-A activity more selectively than non-methylated derivatives. The results suggest that the HTR induced by 5- and 6-FMT may result from increased activity of central 5-HT neurons, probably due to increased 5-HT levels after MAO-A inhibition. This probably results in release of 5-HT with a concomitant increased interaction with postsynaptic 5-HT2 receptors. The present results also indicate the importance of the methyl group to selective MAO-A inhibition by the substrate-analogues tested, and the concomitantly induced animal behavior.

Animals↗
PubMed1995

Involvement of opioid receptors in the antinociception produced by intracerebroventricularly administered spantide in mice.

The antinociceptive effect of intracerebroventricularly (i.c.v.) administered [D-Arg1, D-Trp7,9, Leu11]-substance P (spantide), a non-selective tachykinin antagonist, was examined using the mouse formalin test. Licking behaviour induced by 2% formalin solution in the hindpaw of mice had two peaks, 0-5 min (first phase) and 10-30 min (second phase). I.c.v. spantide produced a dose-dependent antinociception during the first and second phases. The ID50 values were 2.95 (1.59-5.46) nmol for the first phase and 2.87 (1.49-5.52) nmol for the second phase. The antinociceptive effect in the first phase, but not in the second phase produced by spantide was antagonized by pretreatment with naloxone (1.0 mg/kg, i.p.), an opioid receptor antagonist. An opioid binding study using [3H]naloxone revealed that spantide was able to inhibit [3H]naloxone binding to mouse brain membrane preparations. These results suggest that opioid receptor systems in the mouse brain are involved in spantide-induced antinociception during the first phase, but not during the second phase of the formalin-induced nociceptive behaviour.

Amino Acid Sequence↗
PubMed1995

Effects of transient global ischemia and a monoamine oxidase inhibitor ifenprodil on rat brain monoamine metabolism.

Ifenprodil, a cerebral vasodilator and non-competitive glutamate antagonist, is also an anti-ischaemic agent; it has been shown to inhibit both forms of MAO in rat brain and lung (with slightly greater potency towards MAO-A), but it does not inhibit SSAO. The effects of ifenprodil on rat brain regional levels of monoamines and their principal metabolites following transient global ischaemia have been investigated 1 h after reperfusion. Among the three most ischaemically vulnerable brain regions (striatum, hippocampus and cortex), striatal DA, DOPAC, HVA, 5-HT and 5-HIAA levels were the most markedly increased. Simultaneous treatment with ifenprodil during reperfusion reversed the increases in the striatum, except for HVA, to the level similar to those of sham-operated controls. In contrast to the striatum, ifenprodil failed to reverse the increases seen in the cortex and hippocampus.

Animals↗
PubMed1994

Comparison of antagonistic effects of sendide and CP-96,345 on a spinally mediated behavioural response in mice.

Intrathecal administration of the tachykinin NK1 receptor agonists, substance P, physalaemin, septide and [Sar9, Met(O2)11]substance P, elicited a characteristic behavioural response consisting of scratching, biting and licking in mice. The behavioural response induced by substance P was significantly inhibited by simultaneous intrathecal injection of a tachykinin NK1 receptor antagonist, [Tyr6,D-Phe7,D-His9]substance P-(6-11) (sendide), and a non-peptide antagonist, [(2S,3S)-cis-2-(di-phenylmethyl)-N-[(2- methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine](CP-96,345). The duration of the antagonistic effect of sendide was similar to that of CP-96,345. The antagonistic effect of sendide on the response induced by tachykinin NK1 receptor agonists was approximately 1000 times more potent than that of CP-96,345. Neither antagonist inhibited neurokinin A-, D-septide-, neurokinin B- and eledoisin-induced scratching, biting and licking responses. Sendide was without effect on motor performance as measured by the rotarod test, while motor incoordination was elicited only 2 min after intrathecal injection of CP-96,345. These results indicate that sendide and CP-96,345 are selective antagonists of tachykinin NK1 receptors with a long duration of action.

Analgesics↗
PubMed1994

Differential antinociceptive effects of sendide, a NK1-receptor antagonist, and morphine in the capsaicin test.

The peptide NK1-receptor antagonists, sendide and [D-Trp7]sendide, have been evaluated for antinociceptive activity in the capsaicin test. Both peptides, injected intrathecally (i.t.) 5 min prior to intraplantar capsaicin, produced a dose-dependent reduction of the capsaicin-induced paw licking response. Naloxone (4.0 mg/kg) pretreatment did not affect sendide- and [D-Trp7]sendide-induced antinociception, whereas naloxone at a dose of 0.5 mg/kg antagonized the antinociceptive effect of i.t. administered morphine. Conversely, the antinociceptive action induced by both NK1-receptor antagonists was reduced significantly by i.t. co-administration of substance P. Morphine-induced antinociception was not antagonized by co-administration of substance P. These results led us to the understanding of differential action mechanism of NK1-receptor antagonist- and morphine-induced antinociception as assayed by the capsaicin test.

Analgesics↗
PubMed1994

Behavioral activation of neurokinin-1 agonists in relation to enzymatic degradation in the spinal cord.

Intrathecal (i.t.) injection of substance P (SP) induced reciprocal hindlimb scratching directed mainly toward the abdominal regions in mice. This behavior pattern appeared within the first minute after i.t. injection of SP. Similar behavioral effects were produced by i.t. injection of neurokinin (NK)-1 agonists, physalaemin (Phy) and [Sar9,Met(O2)11] SP (Sar-SP). The duration of scratching varied among NK-1 agonists; of the NK-1 agonists used, Phy had the most long-lasting duration of scratching in contrast to SP that had a short duration. The rank order of scratching duration was Phy > Sar-SP > SP. SP was rapidly degraded by the solubilized enzyme extracted from the mouse spinal cord as determined by HPLC. Decay of the scratching response to these NK-1 agonists was parallel with the rate of their degradation by the solubilized enzyme. These results suggest that a relatively long-lasting scratching behavior induced by Phy is mainly attributed to the stability against peptidases in the spinal cord.

Animals↗
PubMed1994

Pharmacological characterisation of NK1 receptor antagonist, [D-Trp7]sendide, on behaviour elicited by substance P in the mouse.

An analogue of sendide, [D-Trp7]sendide, was newly synthetized and evaluated as a putative NK1 receptor antagonist in a mouse behavioural test. Effects of [D-Trp7]sendide on the scratching, biting and licking response induced by substance P (SP), neurokinin A (NK A) and neurokinin B (NK B) was studied after intrathecal injections. When administered simultaneously with SP, an endogenous agonist for NK1 receptors, [D-Trp7]sendide inhibited the behavioural response to this tachykinin in a dose-dependent manner with ID50 value of 11.0 pmol/mouse. The behavioural response elicited by other NK1 receptor agonists, septide and physalaemin, was reduced significantly by a small dose (32.0 pmol) of [D-Trp7]sendide. Large doses (nmol order) of [D-Trp7]sendide were needed to reduce the characteristic behaviour of NK A, an NK2 agonist, NK B, an NK3 agonist and eledoisin, an NK2/NK3 agonist. The duration of the antagonistic effect of [D-Trp7]sendide was relatively longer. In a [3H]labeled SP binding assay using mouse spinal cord membranes, [D-Trp7]sendide potently displaced [3H] labeled SP binding with a Ki value of 0.023 +/- 0.007 nM, which was approximately 140 and 9400 times more potent than that of unlabeled SP and CP-96,345, respectively. These findings suggest that [D-Trp7]sendide interacts selectively with the NK1 receptor in the mouse spinal cord as assayed by the receptor binding and SP-induced behavioural tests.

Amino Acid Sequence↗
PubMed1994

Histological study of the parotid gland in rats treated with oxybutynin hydrochloride.

The purpose of this study was to determine whether oxybutynin hydrochloride (OBHC) induces histological changes in the parotid gland. Thirty male rats were divided into three groups, young (8 weeks), middle-aged (20 weeks) and old (113 weeks). Six rats in each group were given a diet containing OBHC mixed with the standard food. Four rats in each group had free access to standard food as a control. Eight weeks after dieting, all animals were sacrificed and removed their parotid gland. Degeneration, dispersion of basophilic material and transformation of nuclear shape in the acinar cells and atrophy of duct cells were observed in 5 young, 2 middle aged and 6 old rats. There were no appreciable histological changes in young and middle-aged control rats, although an aged-related effect of OBHC was seen in older control animals. These results indicate that chronic treatment with OBHC produces significant effects of aging on histological changes in the parotid gland of rats.

Aging↗