Biomedical subjects

S Tokuyama

Publications and source records attributed to S Tokuyama.

At least 73 records · Page 4Linked to original sources

PubMed1994

Physical dependence produced by dihydroetorphine in mice.

Using various administration schedules, the physical dependence produced by dihydroetorphine (DHE) was compared with that of morphine in mice. Physical dependence, evaluated by naloxone-precipitated withdrawal signs, did not develop following daily treatment with DHE (10, 20, 100 and 1000 micrograms/kg, i.p. or 30, 100 and 1000 ng/mouse, i.c.v.) for 6 d. However, 5 repeated injections of DHE (10 micrograms/kg, i.p.) at 1 or 2 h intervals did produce physical dependence and the dependent state disappeared after 2 h. Accordingly, it was demonstrated that a sufficient degree of antinociceptive activity needed to be maintained, longer than several hours, for the development of physical dependence on DHE and that the duration of the dependent state was very short. In the single dose suppression test, a single dose of DHE completely suppressed the natural withdrawal signs that appeared following abstinence in morphine-dependent animals without reappearance of significant withdrawal signs, indicating the suitability of DHE as a substitute for morphine. The characteristic properties of DHE, the extremely potent antinociceptive effect and minimal dependence, indicate the separation of the antinociceptive effect from dependence, and suggest that it may be possible to develop a novel drug which may be safely used in clinical situations.

Analgesics↗

PubMed1994

Acellular and cellular hemoglobin solutions as vasoconstrictive factor.

The inhibitory effects of acellular and cellular hemoglobin (Hb) solutions on endothelium-dependent vasorelaxation were investigated in rabbit thoracic aortic strips. As acellular Hb solutions, 2,3-diphosphoglycerate (DPG)-depleted Hb and pyridoxylated Hb were examined. Cellular Hb solutions included washed human fresh red cells and liposome Hb encapsulated with pyridoxal-5'-phosphate (PLP). The tissues were precontracted with phenylephrine (PE), after which acetylcholine (ACh) was added to elicit a steady-state relaxation. Acellular Hb solutions cumulatively reversed ACh-induced relaxation, and these inhibitory effects reached a plateau at 10 micrograms/ml. Increasing oxygen affinity by pyridoxylation had little effect on this. In contrast, both red cells and liposome Hb solution showed moderate inhibitory effects, and they reached a plateau at 1 mg/ml. These findings indicate that acellular Hb solutions are more potent inhibitors than cellular Hb solutions by a factor of about 100, and that the encapsulation of Hb is a preferable method to mimic the red cell.

2,3-Diphosphoglycerate↗

PubMed1994

Oxygen transport and in vivo parameters of artificial red cells (ARC).

Artificial red cells (ARC) are prepared by encapsulating Hb with a polymerizable phospholipid. Their physical stability is very high and long-term preservation is possible in the frozen state. We examined the effect of blood parameters on the hematological and biochemical findings in transfused rats. The oxygen transport capacity of ARC in vivo were also tested by exchange transfusion in beagles. The oxygen binding parameters were almost the same as those of red blood cells (i.e., P50, Hill's coefficient, and oxygen transport efficiency (OTE) were 30 mmHg, 2.5, and 30%, respectively). The blood parameters after transfusion showed no significant changes when compared with the control. The oxygen transport capacity was of the same efficiency as red blood cells.

Animals↗

PubMed1993

Antinociceptive effect of dihydroetorphine and its tolerance/dependence liability in mice.

The profile of actions of dihydroetorphine (DHE) concerning antinociception, tolerance and dependence was compared with those of morphine in mice. DHE at 1, 5, 10 or 20 micrograms/kg produced an antinociceptive effect in a dose dependent manner and 10 micrograms/kg was nearly equipotent to that of 10 mg/kg of morphine. The antinociceptive effect of both drugs was completely suppressed by 1 mg/kg of naloxone, while neither 10 mg/kg of naltrindole nor 1 mg/kg of nor-binaltorphimine had any suppressive effect. Mice tolerant to morphine antinociception were tolerant to DHE and vice versa. The naloxone-sensitive, locomotor accelerating activity was progressively enhanced by daily administration of DHE and morphine and a cross reverse tolerance developed between these compounds, suggesting that common mechanisms, especially mediating opioid receptors, underlay the activity enhancement. The development of physical dependence as evidenced by naloxone precipitated withdrawal signs, however, was not observed with daily treatment with DHE, 10, 20 and 100 micrograms/kg for 6 d. Thus, we demonstrated that DHE produces the antinociceptive effect mediated through mu opioid receptors without causing development of a physical dependence, suggesting that it is safe to use in the clinical therapy of patients suffering severe pain such as that accompanying cancer.

Analgesics↗

PubMed1993

Involvement of serotonergic receptor subtypes in the production of antinociception by psychological stress in mice.

Besides the important role of emotional factors in the production of psychological-stress-induced analgesia (PSY-SIA), recent attention to the participation of serotonergic (5-HTnergic) neurons in the fear- and anxiety-evoking mechanism led us to examine the effects of 5-HTnergic ligands on PSY-SIA. Pretreatment of mice with 2.0 to 10 mg/kg of methysergide, a 5-HT receptor antagonist, or 1.0 to 10 mg/kg of buspirone, a 5-HT1A receptor partial agonist, dose-dependently suppressed the production of PSY-SIA. Ritanserin, a 5-HT2 receptor antagonist, 1.0 to 5.0 mg/kg, or Y-25,130, a 5-HT3 receptor antagonist, 0.03 and 0.1 mg/kg, also inhibited PSY-SIA dose-dependently, while (+/-)pindolol, a 5-HT1A/1B receptor antagonist, was ineffective at doses up to 3.0 mg/kg. Furthermore, the suppressive effect of PSY-stress on the development of antinociceptive tolerance to morphine was also antagonized by methysergide, buspirone, ritanserin and Y-25,130, but not by (+/-)pindolol. These results suggest that 5-HT receptor (5-HT1A, 5-HT2 and 5-HT3 but not 5-HT1B)-mediated mechanisms play an important role in the production of PSY-SIA.

Animals↗

PubMed1992

The study on phosphatidylinositol-specific phospholipase C from Bacillus thuringiensis: synthesis of homogeneous substrates, substrate specificity and other properties.

The properties of phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus thuringiensis were studied in detail. The enzyme was extremely thermostable in 0.1% bovine serum albumin and retained 73% of its activity at 100 degrees C for 10 min, while it was labile in the absence of albumin. The enzymatic activity was inhibited by HgCl2 or p-chloromercuriphenylsulfonic acid and restored by dithiothreitol. The kinetic parameters (Km and Vmax) of PI-PLC were determined for the mixed micelle of yeast phosphatidylinositol (PI)/Triton X-100 or sodium deoxycholate. Four PIs having different acyl chains: dilauroylphosphatidylinositol (DLPI), dimyristoylphosphatidylinositol (DMPI), dipalmitoylphosphatidylinositol (DPPI) and dioleoylphosphatidylinositol (DOPI) were synthesized from yeast PI through the processes of deacylation and reacylation, identified by infrared (IR) and Fourier transform nuclear magnetic resonance (FT-NMR) spectra, and subjected to the action of PI-PLC. All the synthetic PIs were hydrolyzed by this enzyme, with DLPI and DMPI being the best substrates. PI-PLC did not catalyze the hydrolysis of the phosphatidylnucleosides 5'-phosphatidylcytidine, 5'-phosphatidyluridine, 5'-phosphatidylthymidine, 5'-phosphatidyladenosine and 5'-phosphatidyl-2'-deoxyadenosine.

Bacillus thuringiensis↗

PubMed1992

Anti-stress effect of ginseng on the inhibition of the development of morphine tolerance in stressed mice.

We examined how the ginseng extract (GE) acts on the antinociceptive effect induced by footshock (FS)-, psychological (PSY)- and forced swimming (SW)-stress (stress-induced analgesia, SIA), and also on the suppression by FS- and PSY-stress of the development of tolerance to morphine in mice. Neither an acute treatment nor 5 daily pretreatments with GE at 100 mg/kg, p.o. affected each SIA. Pretreatment with GE at 100 mg/kg, p.o. for 5 days followed by the treatment in combination with the exposure to stresses for another 5 days caused no appreciable changes in the development of tolerance to FS- and SW-SIA, but suppressed the development of tolerance to PSY-SIA. When mice were pretreated with GE for 5 days and given GE daily prior to morphine at 10 mg/kg/day, with stress exposure for another 5 days, the inhibitory effect of FS-stress on the development of tolerance to morphine was completely eliminated. The present results suggest that GE, by improving the general metabolism in the body, directs toward normalization of the adaptability which is impaired by stress exposure, while not compromising morphine antinociceptive activity or the SIA, another adaptability produced in confrontation to abnormal environmental stimuli. In addition, the differences in the mechanism underlying the FS- and PSY-stress effect which we have previously demonstrated are also reconfirmed.

Analgesics↗

PubMed1992

Blockade by ginseng extract of the development of reverse tolerance to the ambulation-accelerating effect of methamphetamine in mice.

Daily repeated administration of methamphetamine (MAP) developed reverse tolerance to its ambulation-accelerating effect. After pretreatment of mice daily with ginseng extract (GE) for 5 days, concomitant injections of MAP and GE suppressed the development of reverse tolerance to the effect of MAP, although GE itself did not affect the spontaneous motor activity of the naive mice. These results provide evidence that GE may be useful for prevention and therapy of the adverse action of MAP.

Animals↗

PubMed1992

Participation of GABAergic systems in the production of antinociception by various stresses in mice.

Based on the data that diazepam, a benzodiazepine (BZP) receptor agonist, antagonized psychological (PSY)-stress induced analgesia (SIA) without prominent action on footshock (FS)- and forced swimming (SW)-SIA and that BZP receptors are coupled with GABA receptors, we examined how the GABAergic system participates in the production of various SIAs. Muscimol, a GABAA receptor agonist, at doses of 0.25 to 1.0 mg/kg, affected each SIA differently, suppressed PSY-SIA at 0.25 mg/kg but tended to potentiate it at 1.0 mg/kg, potentiated SW-SIA dose-dependently and did not affect FS-SIA at the doses employed. Both bicuculline, a GABAA receptor antagonist, 0.5 to 2.0 mg/kg, and picrotoxin, a Cl- channel blocker, 0.25 to 1.0 mg/kg, dose-dependently suppressed PSY- and FS-SIA. Meanwhile, the effects of both drugs on SW-SIA were less than those on PSY- and FS-SIA, namely, bicuculline slightly inhibited it only at 2.0 mg/kg, and picrotoxin did not produce any appreciable effect even at the highest dose. Baclofen, a GABAB receptor agonist, at 5.0 and 10.0 mg/kg had no influence on each SIA. On the contrary, CGP 35348, a GABAB receptor antagonist at 20 to 100 mg/kg caused the dose-dependent blockade of FS-SIA, but affected neither PSY- nor SW-SIA. The production of PSY- and SW-SIA is attributable to the GABAA receptors/Cl- channel mediated mechanism alone, while that of FS-SIA involves both GABAA and GABAB receptor mediated systems. Thus, GABAergic systems play an important role in the production of each SIA; however, the participation of the receptor subtypes in the mechanism was different from each other.

Analgesia↗

PubMed1992

Characteristics of polylipid/Hb vesicles (ARC) (in vitro and in vivo test).

Polylipid/Hb vesicle, which is polymerized phospholipid vesicles (200 nm) encapsulating concentrated Hb solution, has been established by us as an artificial red cell (ARC). ARC can be easily adjusted to physiological conditions (viscosity, density and oncotic pressure etc) as the same of human blood. Our ARC has excellent blood compatibility (no effect on coagulation, no hemolysis and no red cell aggregation). Neither acute toxicity nor damage of internal organs was confirmed. Oxygen transporting capacity was almost the same as human blood, and the half life in blood stream was ca. 13 hrs.

Animals↗

PubMed1991

The opioid activity and receptor selectivity of fluorinated Leu5 enkephalin analogues in vitro and in vivo.

The opioid activity and the selectivity for opioid receptor (subtypes) of newly synthesized fluorinated enkephalin (Enk) analogues, [2R, 4R], [2R, 4S], [2S, 4S] and [2S, 4R] trifluoro-Leu5-Enk (KKF-31, 32, 33 and 34) were investigated. The inhibitory effect of KKF-compounds on the electrically induced contractions of guinea-pig ileum (GPI) and mouse vas deferens (MVD) were dose-dependent but relatively lower than that of L-Leu5-Enk, except that KKF-34 was rather slightly more potent than L-Leu5-Enk in MVD preparations. In GPI preparations, the pA2 values of naloxone for these compounds were higher than those of naltrindole while the values of naltrindole for KKF-compound were higher than those of naloxone in MVD preparations. Intracerebroventricular KKF-31 and KKF-32 at doses of 20 and 10 nmol/mouse, respectively, produced analgesia comparable to 0.1 nmol Tyr-D-Arg-Phe-Lys-NH2 and 100 nmol Tyr-D-Thr-Gly-Phe-Leu-Thr; however, neither KKF-33 nor 34 produced analgesia up to the doses of 100 nmol/mouse. Both naloxone, 1 mg/kg, i.p., and naltrindole, 10 mg/kg, i.p., antagonized KKF-31- and KKF-32-induced analgesia. The results suggest that the introduction of trifluoromethyl group in Leu5 results in the alternation of the opioid activity and receptor selectivity. Although KKF-33 and KKF-34 possessed a more potent in vitro inhibitory effect than KKF-31 and KKF-32, mediated through mu- and delta-opioid receptors in both preparations, they did not show any appreciable analgesic effect. KKF-31 and KKF-32 produce naloxone- and naltrindole-reversible analgesia irrespective of in vitro mu- and delta-opioid activity.

Analgesics↗

PubMed1991

Participation of an alpha 2-mediated mechanism in the production of forced swimming-stress induced analgesia in mice.

In mice, both swimming-stress induced analgesia (SW-SIA) and clonidine (CLO) analgesia were dose dependently antagonized by yohimbine, an alpha 2-adrenoceptor antagonist, but not by naloxone, an opioid mu-antagonist. SW-SIA was potentiated by subanalgesic dose of CLO, and CLO analgesia was enhanced by SW-SIA. Animals tolerant to CLO analgesia were tolerant to SW-SIA, in contrast, CLO analgesia was potentiated in SW-SIA tolerant mice. Thus, SW-SIA and CLO analgesia partially share a common alpha 2-adrenergic-dependent mechanism, for their production.

Analgesia↗

PubMed1991

Further evidence for the participation of an alpha 2-adrenoceptor mediated mechanism in the production of forced swimming-stress induced analgesia in mice.

Subanalgesic dose, 0.01 to 0.25 mg/kg, of clonidine (CLO), an alpha 2-adrenoceptor agonist, potentiated forced swimming (SW) stress induced analgesia (SIA) and suppressed psychological (PSY)-SIA in a dose dependent manner but did not affect foot-shock (FS)-SIA. Daily exposure to each stress rapidly developed tolerance, and the development was suppressed by daily concomitant subanalgesic dose of CLO in SW-SIA but not in FS- and PSY-SIA. Meanwhile, SW-stress, applied after injection of CLO, 1 mg/kg, potentiated the analgesic effect of CLO and suppressed the development of tolerance to the effect. On the other hand, FS- and PSY-stress did not affect CLO analgesia and failed to block the tolerance development. These results provide further evidence that alpha 2-adrenergic mechanism is involved in the production of SW-SIA.

Analgesia↗

PubMed1990

Further evidence for the implication of a kappa-opioid receptor mechanism in the production of psychological stress-induced analgesia.

The analgesic effect induced by exposure to psychological stress, using a communication box (psychological stress-induced analgesia, PSY-SIA), was completely antagonized by 10 min pretreatment with 0.5, 1 and 2 mg/kg of nor-binaltorphimine and with 0.5 and 1 mg/kg of Mr2266, selective kappa-opioid receptor antagonists, in the tail pinch method. Neither footshock (FS)- nor forced swimming (SW)-SIA was affected by these antagonists. The selective delta-opioid receptor antagonist naltrindole, at doses up to 20 mg/kg, had no appreciable effect on PSY-SIA. Daily morphine treatment, 10 mg/kg, s.c., resulted in tolerance to the analgesic effect, and concurrent exposure to PSY-stress suppressed the development of morphine tolerance. The substitution of treatment with U-50,488H for PSY-stress still resulted in analgesia on the initial day; and likewise, the suppression by U-50,488H of the development of morphine tolerance was replicated by PSY-stress. Pretreatment with nor-binaltorphimine antagonized the suppressive effect of PSY-stress on the development of morphine tolerance without affecting the analgesic effect of morphine per se. These results provide further evidence that PSY-SIA involves the mediation by kappa-opioid receptor mechanisms.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1989

Release of substance P by intrathecal KK-3, a newly synthesized Leu-enkephalin derivative.

Intrathecal (IT) injection of KK-3, a leucine-enkephalin analogue with weak, naloxone-reversible analgesic effect, produced behavior consisting of scratching, biting, licking and characteristic convulsion-like symptoms in mice. Naloxone or Mr2266 did not affect the behavior, suggesting a difference in the mechanisms for the production of the behavior and the analgesic effect. The behavior, except the convulsive symptom and the lag time of a couple of min for onset of the behavior, are quite similar to that elicited by IT substance P (SP). D-Pro2-D-Trp7,9-substance P, a SP antagonist, completely suppressed all the behavior induced by KK-3, indicating that the behavior is attributable to SP. By radioimmunoassay, it was found that SP was released by stimulation with KK-3 from the isolated spinal cord preparation of newborn rat. Intrathecal pretreatment with capsaicin, a depleter of SP, suppressed the KK-3-induced behavior, but did not affect the SP-evoked behavior. These results suggest that KK-3 acts as a releaser of SP in the spinal dorsal horn, and consequently produces SP-like behavior. Thus, a novel pharmacological action, the release of substance P from spinal cord by the IT injection of endogenous opioid peptide analogue, was demonstrated.

Animals↗

PubMed1989

Blockade of the development of analgesic tolerance to morphine by psychological stress through benzodiazepine receptor mediated mechanism.

beta-Carboline-3-carboxylic acid ethyl ester (beta-CCE) dose-dependently potentiated psychological-stress induced analgesia (PSY-SIA), and the effect was reversed by diazepam. Concurrent exposure to PSY stress or concomitant treatment with beta-CCE blocked the development of analgesic tolerance to morphine; the effect of PSY stress was antagonized by diazepam, and that of beta-CCE was reversed by Ro 15-1788. These results suggest that psychological factors which are mediated through benzodiazepine receptors are involved in the mechanism for blocking the development of analgesic tolerance to morphine by PSY stress.

Analgesia↗

PubMed1988

Distinctive implication of emotional factors in various types of stress-induced analgesia.

Diazepam, an antianxietic agent, antagonized the stress-induced analgesia (SIA) distinctively depending on the characteristics of the stress. Psychological (PSY, using communication box)-SIA was completely blocked by 1 or 2 mg/kg of diazepam in the tail pinch (TP) method, but not antagonized by 1 mg/kg of the drug in the tail flick test. Swimming-SIA was resistant to diazepam in both methods and footshock-SIA was only suppressed slightly by 2 mg/kg in the TP method. Thus, emotional factors play an essential role in the production of PSY-SIA, although the participation of the factors in the other SIAs can not be excluded.

Analgesia↗

PubMed1987

Implication of endogenous opioid mechanism in the production of the antinociceptive effect induced by psychological stress in mice.

Psychological (PSY) stress using the communication box produced a short-lasting antinociceptive effect which was less potent than that induced by physical stress such as footshock (FS) and forced swimming (SW) in mice. Naloxone completely antagonized PSY-stress induced analgesia (SIA) when the analgesia was measured by the tail pinch (TP) method; however, the antagonist did not reverse the effect in the tail flick (TF) assay. On the other hand, FS-SIA was antagonized by naloxone in both methods, while naloxone failed to reverse SW-SIA in either TF or TP assessment. Daily exposure to psychological stress developed tolerance to the analgesia. One-way cross-tolerance between PSY-SIA and morphine and the naloxone antagonism of PSY-SIA by the tail pinch method lead to the suggestion that an endogenous opioid system may be involved in the underlying mechanism for its production. On the contrary, from the findings of cross-tolerance between SW- or FS-SIA and the lack of naloxone antagonism in the TF method, the involvement of a more complicated mechanism is suggested in PSY-SIA. In both tests, U-50488H, a selective kappa-agonist, produced profound analgesia; however, no appreciable antagonism of naloxone was found in the TF test, whereas the effect was completely blocked by naloxone in the TP test. From the similarity in naloxone antagonism of PSY-stress and U-50488H induced analgesia, the participation of a common mechanism which may be mediated by kappa-opioid receptors, is suggested in the production of PSY-SIA.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗