Kaposi's sarcoma, vascular permeability, and scientific integrity.
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Animals↗
Biomedical subjects
S Sakurada
Publications and source records attributed to S Sakurada.
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↗
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↗
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↗
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↗
Changes in hypothalamic temperature of rats after daily exposure to heat at a fixed time.
Rats were subjected to an ambient temperature (Ta) of 33 degrees C for ca. 5 h during the last half of the dark phase for 5, 14 or 28 consecutive days (heat-exposed rats, HE), while control rats were kept at a constant Ta of 24 degrees C. After the heat exposure schedule, the levels of hypothalamic temperature (T(hy)) as an index of body core temperature in the HE were significantly lower than those of the controls for 2-4 h in the last half of the dark phase. The low levels of T(hy) persisted during the specific period for 1, 3 and 6 days after the end of the 5-, 14- and 28-day heat exposure schedules, respectively. These results confirm that, in rats subjected to daily heat exposure for ca. 5 h at a fixed time per day, their T(hy) falls during the period when the rats were previously exposed to heat, and suggest that the duration of the specific T(hy) change observed after completing the heat exposure schedule depends on the length of the heat exposure schedule.
Animals↗
Day-night changes of body temperature and feeding activity in heat-acclimated rats.
Male Wistar rats were divided into two groups. The controls (CN) were kept at a constant ambient temperature (Ta) of 24 degrees C throughout the experiment. Heat-acclimated rats (HA) were subjected to Ta of 33 degrees C in the last half of the dark phase for 16 consecutive days. After the schedule was terminated, hypothalamic temperature (Thy), oxygen consumption (VO2), heat loss, and feeding activity were measured for the following 2 days at Ta of 24 degrees C with a direct calorimeter in constant darkness. Hypothalamic temperature, VO2, and heat loss of the HA were significantly lower than those of the CN for 3-4 h during the period when the rats had been previously exposed to heat. Feeding activity during the specific period was significantly less in the HA than in the CN only on the first day. Under starved conditions, the decreases of Thy and VO2 during the previous heat exposure time were consistent in the HA. The results suggest that body core temperature and feeding behavior decrease during the previous heat exposure time in rats after subjection to repeated heat exposure at a fixed time daily. The characteristic fall in body core temperature is mainly attributed to the reduction of VO2. It also seems that a decrease in postprandial thermogenesis is not a predominant contributor to the depression of VO2 during the previous heat exposure time in heat-acclimated rats.
Acclimatization↗
Role of intracellular SOD in protecting human leukemic and cancer cells against superoxide and radiation.
Many anticancer drugs have been shown to produce superoxide anion (O2.-) and seem to involve O2.- in their mode of action. Ionizing radiation provokes the decomposition reaction of water, producing a variety of reactive oxygen species, including O2.-. The finding that cancer cells are generally low in SOD activity may offer a theoretical base for radiation therapy and chemotherapy. The purpose of this study was to examine the protective effect of intracellular SOD against cytotoxicity induced by O2.- or radiation and to investigate whether exogenous SOD can protect cells from O2.-(-) and radiation-induced cytotoxicity. For this purpose, xanthine (X) and xanthine oxidase (XOD) were employed as an O2.- (-)generating system, and a linear accelerator was used for ionizing radiation. Cytotoxicity against monolayer cancer cell lines and leukemic cell lines was estimated by measuring the release of lactate dehydrogenase from these cells. The results revealed that the resistibilites to X- and XOD-generated O2.- and radiation correlated with intracellular Cu. Zn-SOD levels and that exogenous SOD could only slightly reduce X- and XOD-induced cytotoxicity while having no influence on radiation-induced cytotoxicity. Thus, intracellular SOD may play a central role in protecting cancer cells against reactive oxygen species generated by anticancer drugs and radiation.
Carcinoma, Squamous Cell↗
Persisting changes in the 24-hour profile of locomotor activity by daily activity restriction in rats.
Male Wistar rats were acclimated to cages with running wheels. Then, the running time of rats were limited to the last 3 (WR3) or 6 (WR6) h of the dark phase. After a 2-week activity restriction, the rats were again allowed access to the wheel freely. In the WR3 or WR6, wheel revolutions for the last 3 or 6 h of the dark phase was significantly greater after the activity restriction than before. The results suggest that, in rats, voluntary running limited to a fixed time daily alters the distributions of locomotor activity in a day, i.e., running activity increases during the period when the rats had been previously allowed to exercise.
Activity Cycles↗
Antinociceptive effects in the formalin and capsaicin tests after intrathecal administration of substance P analogues in mice.
The antinociceptive effect of substance P- and substance P-(6-11) analogues containing D-histidine (D-His) in position 9 was examined in mice in the formalin and capsaicin tests. [D-Arg1,D-Trp7,9,Leu11]substance P (spantide) was used as reference drug. Intrathecal injections of the [D-His9]substance P and substance P-(6-11) analogues at 4.0 nmol resulted in no significant antinociception as measured in the 2.0% formalin test, although spantide was antinociceptive in the early and late phases. The early response induced by 0.0625% formalin was reduced significantly by the [D-His9]substance P and substance P-(6-11) analogues at 4.0 nmol, which were less potent than spantide. The antinociception induced by spantide and a few analogues of substance P and substance P-(6-11) containing D-His was reversed significantly by pretreatment with 2 mg/kg naloxone, an opioid antagonist. The nociceptive response to capsaicin was inhibited significantly by lower doses (2.0 nmol) of the analogues. The antinociception evoked by the analogues was not reversed by naloxone in the capsaicin test. Co-injection of the [D-His9]substance P and substance P-(6-11) analogues at 2.0 nmol selectively decreased substance P-induced licking, biting and scratching without affecting the behavioural responses to NK2 and NK3 receptor agonists. Spantide non-selectively inhibited the behavioural responses produced by not only substance P, but also neurokinin A, D-septide, neurokinin B and eledoisin. The data show that the capsaicin test may be a better method for evaluating neurokinin antagonists than the formalin test.
Analgesics↗
A selective and extremely potent antagonist of the neurokinin-1 receptor.
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Analgesics↗
Spantide-induced antinociception in the opioid mechanism.
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Analgesics↗
Correlation of oncostatin M secretion by human retrovirus-infected cells with potent growth stimulation of cultured spindle cells from AIDS-Kaposi's sarcoma.
Oncostatin M (OM), a 30-kDa glycoprotein, recently was identified as a major growth-promoting factor in the conditioned medium (CM) of the 38-0 cell line, a CD4,+ chronically human T lymphotropic virus type (HTLV)-II-infected, transformed T cell line. CM 38-0 induced the proliferation of spindle cells cultured in vitro from AIDS-associated Kaposi's sarcoma (AIDS-KS) cells. To determine how much of the AIDS-KS cell growth activity present in 38-0 CM was because of the presence of OM, we depleted OM by using specific mAb-affinity chromatography. OM purified from this CM stimulated AIDS-KS cell growth in a concentration-dependent fashion. The effluent, completely depleted of OM, failed to induce growth of AIDS-KS cells. To detect the constitutive release of OM by cells acutely or chronically infected with either HTLV-I, HTLV-II, or HIV-1, we utilized an enzyme-linked immunoassay. Whereas the chronically infected cells released significant levels of OM, the acutely infected cells released little or no OM. The presence of OM in HIV-1-infected T-cell CM correlated completely with AIDS-KS cell growth activity. Infrequently, low level AIDS-KS cell growth activity was seen in the absence of OM. This correlated with relatively high levels of IL-6 in the CM. In a CM-containing OM in the absence of detectable IL-6, a neutralizing antibody to OM completely abrogated KS cell growth activity. The presence of specific oncostatin M receptors on the KS cell lines was confirmed by cross-linking experiments. The results shown here suggest that T cells chronically infected with HIV-1 can secrete OM, which may play a role in the initiation or progression of AIDS-KS lesions, either alone, or in concert with IL-6.
Acquired Immunodeficiency Syndrome↗
Antinociception induced by CP 96,345, a non-peptide NK-1 receptor antagonist, in the mouse formalin and capsaicin tests.
The non-peptide NK-1 receptor antagonist, CP 96,345, has been evaluated for antinociceptive activity in two chemical pain models in the mouse. CP 96,345, injected intrathecally (i.t.) 5 min prior to 2.0% formalin, produced significant antinociception in both the early and late phases of the formalin-induced paw licking procedure. Antinociception could also be observed during the late phase by treatment with CP 96,345 after formalin. In the capsaicin (CAP) test, i.t. injection of CP 96,345 produced a dose-dependent reduction of the paw-licking response at doses much less than antinociceptive doses in the formalin test. Naloxone did not affect antinociception in either test. CP 96,345 evoked a reversible deficit in motor performance as assayed by the rotarod test. The results indicate that i.t. CP 96,345 is antinociceptive in the capsaicin test at doses showing no overt behavioural effects but there is an overlap in doses producing antinociceptive and motor effects in the formalin test.
Analgesics↗
Tolerance and cross-tolerance to the antinociceptive effects of [D-Arg2]-dermorphin tetrapeptide analogue and morphine.
Rats were given repeated subcutaneous injections of [D-Arg2, Sar4]-dermorphin (1-4) [DAS-DER-(1-4)] and/or morphine over a period of 4 or 7 days. Antinociception was determined at 90 min for DAS-DER (1-4) and 30 min for morphine after each morning injection (9:00 a.m.), using the tail-flick and digit pinching tests in rats. Subcutaneous administration of DAS-DER (1-4) and morphine produced the development of antinociceptive tolerance, respectively. A marked tolerance to DAS-DER (1-4) and morphine was seen in rats made tolerant to morphine. However, administration of morphine produced no significant decrement in the antinociceptive activity in rats made tolerant to DAS-DER (1-4). These results suggest that the site of action of DAS-DER (1-4) may be more limited than that of morphine in the nociceptive pathways, for lack of its antinociceptive efficacy in morphine-tolerant rats.
Amino Acid Sequence↗
Possible involvement of the spinal substance P system in pilocarpine-induced scratching in mice.
IT administration of pilocarpine in the spinal subarachnoid space of mice produced a dose-related hindlimb scratching. When coadministered with substance P IT, the pilocarpine-induced scratches were enhanced by high doses of substance P but not by subthreshold doses. This characteristic behavioral response was inhibited dose dependently by IT coadministration of spantide [D-Arg1, D-Trp7,9,Leu11] substance P. Significant antagonistic effects of [D-Phe7,D-His9] substance P (6-11), a selective antagonist for substance P receptors, and substance P (1-7), a substance P N-terminal fragment, were observed against the pilocarpine-induced scratching. Pretreatment with substance P antiserum resulted in the reduction of the response to pilocarpine. When coadministered IT with pilocarpine, atropine potently inhibited pilocarpine-induced scratching. These results demonstrate that not only muscarinic receptors but also substance P-containing neurons in the mouse spinal cord may be involved in elicitation of the scratching behavior following IT injection of pilocarpine.
Afferent Pathways↗
Theophylline-induced nociceptive behavioral response in mice: possible indirect interaction with spinal N-methyl-D-aspartate receptors.
Intrathecal administration of an adenosine receptor antagonist, theophylline, elicited nociceptive behavior such as licking, biting and scratching in mice. This behavioral response was dose-dependently reduced by simultaneous injection of an adenosine receptor agonist, 5'-N6-ethylcarboxamidoadenosine, or a selective N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosphonovalerate. This theophylline-induced behavior was not significantly reduced by the substance P (SP) analogue, the neurokinin receptor antagonist, [D-Arg1, D-Trp7.9, Leu11]SP (spantide). These results suggest the possibility that theophylline-induced nociceptive behavior may be mediated through interactions with both spinal adenosine- and NMDA receptors separately, or only through interaction(s) with adenosine receptors localized on the axon terminals of excitatory amino acid neurons. Present data have failed to reveal involvement of SP.
2-Amino-5-phosphonovalerate↗
Shivering and nonshivering thermogenic responses of rats subjected to different patterns of heat acclimation.
Male Wistar rats were divided into five groups: a control group kept at an ambient temperature of 24 degrees C for 14 days, and four heat-acclimated groups (two groups subjected to a constant ambient temperature of 33 degrees C for 4 days or 14 days (HC-14) immediately preceding the measurement; and another two groups subjected to an ambient temperature of 33 degrees C for about 5 h once a day for 4 days, or 14 days (HI-14) just prior to the measurement). After the completion of the schedule, the rats were placed in a temperature-controlled chamber. Hypothalamic (Thy) and interscapular brown adipose tissue (TBAT) temperatures, oxygen consumption (VO2), and shivering activity were measured during a gradual fall in temperature of a water jacket surrounding the chamber (TW) from 30 to 10 degrees C at a constant rate of 0.18 degree C/min. During the fall in TW, VO2 and TBAT increased significantly and shivering was induced without associate changes in Thy in all groups. TW at the onset of a rise in metabolic heat production (onset of cold-induced thermogenesis) coincided with that at the onset of a rise in TBAT (onset of BAT thermogenesis), but was significantly higher than that at the onset of shivering. In HC-14 and HI-14 rats, TWS at the onset of cold-induced thermogenesis and BAT thermogenesis were significantly higher than those in control rats, whereas TWS at the onset of shivering were not different from those in control rats. The onset of cold-induced thermogenesis did not change after the 4-day heat exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
Acclimatization↗