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The Kampo (Japanese herbal) medicine "Juzen-Taiho-To" (TJ-48), which was prepared by decocting a concoction (formula), contains ten kinds of herbs and has several immunostimulating activities. In order to determine the contribution of each herbal component, the complement-activating and mitogenic activities of the hot water extract as well as the polysaccharide fraction from each herb were tested. Hot water extracts of Glycyrrhizae radix, Astragali radix, and Atractylodes lanceae rhizoma showed significant mitogenic activity whereas that of Cinnamomi cortex showed potent complement-activating activity. However, the exclusion of any single component herb whether active or not on its own did not result in a loss or an increase of the overall activity of TJ-48. The polysaccharide fraction from Glycyrrhizae radix showed the most potent of both activities among the same fractions from the other nine herbs, and reduced both activities after periodate oxidation, thus indicating that the carbohydrate moiety may contribute to both activities.

"Juzen-Taiho-To" (TJ-48), which is a kampo (Japanese herbal) medicine prepared by decocting a prescription of ten kinds of herbs, has several immunostimulating activities. In order to characterize the active substances for anti-complementary and mitogenic activities, TJ-48 was fractionated. Anti-complementary activity was observed in the water- and methanol-insoluble fraction (F-2) and the crude polysaccharide fraction (F-5), whereas mitogenic activity was only found in F-5. However, other low molecular mass fractions did not show both activities. Methylation analysis indicated that F-2 mainly contained amylopectin-like polysaccharides. Both Pronase digestion and periodate oxidation decreased the anti-complementary activity of F-2, and the beta-amylase-resistant fraction of F-2 still retained the potent anti-complementary activity. When F-5, which has the most potent of both activities, was further fractionated, only the major acidic polysaccharide fraction, F-5-2, showed potent mitogenic activity. Endo-alpha-(1----4)-polygalacturonase digestion showed that F-5-2 mainly contained pectic polysaccharides, and the endo-polygalacturonase treatment of F-5-2 reduced the mitogenic activity but not the anti-complementary activity. F-2 and F-5 each activated the complement system by a different mode of action.

D-phenylalanine (DPA) is known to block the activity of carboxypeptidase, an enzyme which degrades enkephalins, endogenous morphine-like substances. Therefore, it is considered that DPA administered as an inhibiting drug of this degrading enzyme might prolong analgesia induced by acupuncture. 1) Thirty patients suffering from chronic low back pain were treated with acupuncture 30 minutes after the oral administration of 4.0 grams of DPA. The results were: excellent in 7 cases, good in 11, fair in 6 and poor in 6. Cases graded excellent and good were then compared with a placebo group. The effect was increased 26% in the DPA-acupuncture group, which shows no statistically significant difference (P less than 0.1). 2) In 56 patients, tooth extraction was performed under acupuncture anesthesia: 18 had received 4.0 gram of DPA (P.O.) 30 minutes earlier. The results were excellent in 8, good in 6, fair in 3, and poor in 1. The excellent and good cases were compared with 38 placebo group cases. The effect in the DPA-acupuncture anesthesia group was significantly increased by 35% (P less than 0.01). 3) In order to determine the optimum time for the administration of DPA, two schedules of administration were compared. [1] DPA was given on the previous day in three 0.5 gram doses (26 cases). [2] A single 4 gram dose was administered 30 minutes before treatment (30 cases). The results from the "excellent", "good" and "fair" cases showed a 16% increase in effectiveness when DPA was administered the day before, not a statistically significant difference (P less than 0.1), but a clear tendency to increase was observed. The above findings show that DPA has an enhancing effect on acupuncture analgesia and anesthesia in clinical practice.

Gomisin A (TJN-101) is one of the lignan components isolated from Schisandra Fruits and expected to have some efficacies in clinical treatment of hepatitis. The serum concentrations of TJN-101 and Met. B, which was identified as a demethylenated substance and one of the major metabolites of TJN-101 in rats, were investigated. After intravenous administration at doses of 1.6, 4.0 and 10 mg/kg of body weight, the serum concentration of TJN-101 decreased biphasically, and the terminal elimination half-life at each dose was about 70 min. Dose-dependency was observed for the area under the concentration-time curve (AUC). On the other hand, the serum concentration of TJN-101 increased rapidly and reached maximum within 15 to 30 min when administered orally. This result was supported by the in situ roop method. The Cmax and the AUC values were not exactly dose-dependent, but the values increased with a dose-up of TJN-101. The biotransformation of TJN-101 to Met. B, was very rapid in both intravenous and oral administrations. The AUC value of Met. B after oral administration of TJN-101 at a dose of 1.6 mg/kg was relatively larger than any other dosages. It suggested that TJN-101 was extensively underwent the first pass effect in rats. More than 80% of TJN-101 was bound with rat serum protein in vitro and in vivo. Therefore, it seems to be necessary to pay attention when it was administered concurrently with high protein binding drugs.

ハリの鎮痛効果を増強する物質とされるD-フェニルアラニン (D-phenylalanine) を, 抜歯術に前投薬として応用し, その効果を検討した。方法はハリ麻酔単独で行った対照群31例と, ハリ麻酔30分前にD-フェニルアラニンを, 前投薬した試験群9例の抜歯術におけるハリ麻酔効果を比較することにより行った。対照群, 試験群ともに, 抜去歯に合わせて選穴したツボに, 中国針を刺針してハリ麻酔器に接続し, 約30分の誘導時間を経て抜歯術を行った。そしてそのハリ麻酔効果を2群間で比較した。効果判定はスコア1から5に分類し, それを著効・有効・やや有効・無効に判定した。その結果, 対照群のハリ麻酔成功率32%に対し, D-フェニルアラニンを前投薬した試験群の方が, 78%とハリ麻酔効果がより優れていた。

In order to disclose the effect of “KANPO-YAKU” on immune responses, we investigated the induction of anti-SRBC response (PFC assay) in the spleen cells of BDF1 female mice which received Tsumura-Juzentaihoto (TJ-48) . TJ-48 induced an augmentation of anti-SRBC response by oral administration once a day for 7 consecutive days in a dose dependent manner. The maximum induction of anti-SRBC response was seen by 7 days-administration of TJ-48 (2 g/kg/day) and no further increase was obtained by longer treatment. After withdrawing TJ-48, the augmentation of anti-SRBC response was maintained for 3 days and disappeared by 7 days after the withdrawal. The anti-SRBC response was enhanced whether immunization with SRBC was done in vivo or in vitro.

The effects of wuweizisu C, a lignan component of schizandra fruits, on liver injuries induced by carbon tetrachloride (CCl4), d-galactosamine and dl-ethionine were investigated by means of serum-biochemical and histopathological examinations in rats. Pretreatment or combined administration of wuweizisu C dose-dependently reduced the elevation of serum transaminase activity and histological changes such as fatty degeneration, cell necrosis, inflammatory cell infiltration, etc., which were caused by the single administration of 1 ml/kg, p.o., or the repeated administration of 0.2 ml/kg, s.c., daily for 4 days of CCl4, respectively. The effects of wuweizisu C on the liver injuries induced by a low dose (200 mg/kg, i.p.) and a high dose (400 mg/kg, i.p.) of d-galactosamine were compared with those of uridine. Wuweizisu C significantly lowered the rise of serum transaminase activity after the administration of a low dose of d-galactosamine in the serum-biochemical analysis. A tendency was also shown to inhibit cell necrosis and inflammatory cell infiltration caused by both doses of d-galactosamine in the histopathological examination. On the other hand, uridine markedly repaired the serum-biochemical and histopathological changes after the administrations of both doses of d-galactosamine. Also wuweizisu C cured the liver injury by the repeated administration of 150 mg/kg, i.p., daily for 4 days of d-galactosamine. After the repeated administration of 250 mg/kg, s.c., daily for 4 days of ethionine, liver cell atrophy, diffuse fatty degeneration and decrease of serum triglyceride were observed, but not cell necrosis. Wuweizisu C dose-dependently inhibited fatty degeneration and decrease of serum triglyceride. These findings suggest that wuweizisu C can be protective and/or therapeutic on hepatocellular phenomena such as cell necrosis, fatty degeneration, inflammatory cell infiltration, etc., in human hepatitis.

The effect of one of Kampo prescriptions, Tsumura Juzentaihoto (TJ-48), on phagocytes was investigated in BALB/c mice.The oral administration of TJ-48 for 3 to 5 days resulted in the enhanced phagocytic activity of peritoneal exudate cells (PEC) and bone marrow cells (BMC) and the maximum increase was observed at 2 g/kg/day of TJ-48. The enhanced phagocytosis was maintained for 5 days after the withdrawal of TJ-48 and returned to the basal level on day 7. A large increase of chemiluminescence was obtained in PEG from mice given TJ-48 orally for 7 days. Moreover, TJ-48 showed the direct activatingeffect on the phagocytosis of PEC and BMC in in vitro assay.

われわれは, さきに, D-フェニルアラニン (DPA) が, 鍼鎮痛効果を増強することを疼痛閾値の上昇より実験的に立証したことを報告してきた。今回は, 当麻酔科外来での慢性腰下肢痛患者を対象にDPAの術前投与法の違いによる効果を検討した。すなわち, 第I法は前日投与群 (1.5g 分3), 第II法は当日投与群 (4g) とし, これを偽薬投与群の設定により, 二重盲検法にて検討した。対象は罹病期間が3ヵ月以上の慢性腰下肢痛56例で, DPAの投与方法を2つに分けた。その (1) は, 1.5gを3回 (鍼治療前日の夕食後0.5g, 就寝前0.5g, 治療当日の朝食後0.5g) に分けて行い, 投与方法 (2) は, 4g (鍼治療前30分) を経口投与した。鍼治療は低周波置鍼療法を用いた。26例に対しては, (1) の投与方法で行い, 30例に対しては (2) の投与方法で行った。各々について「DPA+鍼」を2回,「偽薬+鍼」を2回, 計4回行い「直後効果」を数値スケール法によって両群を比較した。一方, ボランティア3名にDPA 4g・1.5gを内服させ, 2時間後, 4時間後及び翌月の血漿フェニルアラニンの経時的変動を調べた。その結果, 投与方法 (1) では,「DPA+鍼」(26例) 著効7.8%, 有効69.2%, やや有効19.2%であり (偽薬群に比べて有意), 投与方法 (2) によれば,「DPA+鍼」(30例) 著効23%, 有効37%, やや有効20%, 無効20%であった (偽薬群に比べて有意)。投与方法を比較すると, (2) より (1) の方が, 著効および有効を合わせると17%の増強を認めた。血漿フェニルアラニンの変動は4gの場合2時間～4時間後に高値を示し1.5gの場合は2時間後に高値を示した。われわれは, DPAの投与方法 (投与時期と投与分量) に関して臨床的な検討を行った。すなわち, 投与 (1) の方法と, 投与 (2) の方法との効果を比較すると, 慢性腰下肢痛における鍼鎮痛効果は, 当日投与よりも前日投与の方が, より効果的である傾向がわかった。症例数が少ないために再検討の余地はあるが, アメリカのエーレンプライスの提唱どおりDPAが slow onset, long acting に効果を発揮することに鑑み, 前日から分割して投与する方が望ましいと言える。

It has been demonstrated that TJ-8007 (Tsumura-Zokumeito, A traditional Chinese medicine) has a protective effect against cerebral anoxia. This study was done to elucidate the protective mechanism of TJ-8007 against cerebral ischemia and anoxia. TJ-8007 (0.3 approximately 3.0 g/kg, p.o.) inhibited the rise in the cumulative mortality rate after ligation of the bilateral carotid artery (BCA) in mice. TJ-8007 also significantly prolonged the survival time at the dose of 3.0 g/kg, p.o. However, TJ-8007 (1.0 or 3.0 g/kg, p.o.) did not affect the mean survival time after ligation of BCA in Mongolian gerbils and the gasping movement in a decapitated mouse head that served as a complete ischemic model. Ifenprodil (30 mg/kg, p.o.) also showed the protective effect only against ischemic death after ligation of BCA in mice. TJ-8007 (1.0 or 3.0 g/kg, p.o.) increased the vertebral blood flow, but showed no effect on the internal carotid blood flow in anesthetized dogs. These results suggest that the mechanism for the cerebral protective effect of TJ-8007 may be due to its ameliorating action on the cerebral circulation.

Physical dependence liability of chlorphenesin carbamate (CPC) was studied in parallel with phenobarbital-Na (PB). Beagle dogs were used and the overall duration of the experiment was 85 days, i.e. the first dosing period was 42 dyas (6 weeks) in which drugs were repeatedly administered orally once daily, followed by a withdrawal period (7 days), the second dosing period was continued from the 50th-78th day in which the form and schedule of drug administration was as in the first dosing period. The last 79th to 85th days were used for substitution experiments. In both dosing periods, PB but not CPC showed signs of tolerance formation. Severe withdrawal syndrome was observed in PB administered dogs whereas there were no changes of behavior observed in CPC-dogs by withdrawal and substitution procedures, respectively. CPC apparently does not have a physical dependence liability.

Experiments were performed to investigate the effects of TJ-41 on spermatogenic disorders under current treatment with adriamycin (ADR). Male ICR mice were intraperitoneally injected with ADR at the dose of 0.15 mg/kg, twice a week for 5 weeks. Simultaneously, these mice were orally administered TJ-41 at the dose of 1, 2 or 4 g/kg for 12 weeks. The effects of TJ-41 were evaluated by histological analysis of germ cells in the testis at 7 weeks after the last injection of ADR. TJ-41 at a dose of 4 g/kg significantly inhibited the decrease of testis weight in mice treated with ADR. TJ-41 at doses of 1 and 4 g/kg significantly decreased the proportion of seminiferous tubules without germ cells as compared with the ADR-treated group. On the other hand, TJ-41 at doses of 1 and 4 g/kg significantly increased the proportion of normal seminiferous tubules and the Sertoli cell ratio of spermatocytes as compared with the ADR-treated group. These results indicate that TJ-41 may qualitatively and quantitatively protect against the decrease of germ cells in the testis of mice treated with ADR.

TJN-101 ((+)-(6S,7S,R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy -6,7-dimethyl-10,11-methylenedioxy-6-dibenzo[a,c]cyclooctenol) is one of the lignan compounds isolated from Schisandra fruits. 1) Effect of TJN-101 on liver fibrosis was investigated in rats which were injected with CCl4 (1 ml/kg) subcutaneously twice a week for 12 weeks. TJN-101 was given orally at the dose of 10 or 30 mg/kg/day for 6 or 3 weeks beginning on the 6th or 9th week after the start of CCl4-intoxication, respectively. The elevations of serum transaminase activities and the increase of liver 4-hydroxyproline content were observed depending on the period of CCl4-intoxication. These changes were marked on the 9th and 12th weeks after. In the histopathological study, the degenerative fatty change on the 6th week after and the formation of pseudolobule caused by fibrosis proliferation on the 9th or 12th week after were mainly observed. When rats were treated with TJN-101, the abnormalities in biochemical parameters and the fibrosis proliferation caused by CCl4-intoxication were improved. 2) Chronic liver injury was induced by the treatment with CCl4 (1 ml/kg) subcutaneously twice a week for 10 weeks to investigate the effect of TJN-101 on liver regeneration after partial hepatectomy. TJN-101, which was given orally at the dose of 10, 30 or 100 mg/kg/day for 6 days from the 1st day after partial hepatectomy, dose-dependently increased the liver regeneration rate and improved the serum BSP retention rate. These results suggest that TJN-101 suppresses the fibrosis proliferation and accelerates both the liver regeneration and the recovery of liver function after partial hepatectomy in chronic liver injury.

Adult male rats were administered morphine twice a day for 45 days and the effects of morphine on the copulation rate, the weight of various organs, and on the hypothalamic-pituitary-gonadal axis were examined. Morphine administered rats showed a loss of weight, hypertrophy of the adrenals, decreased weight of accessory sex organs, low sperm count, and decreased copulation rate. The contents of the luteinizing hormone releasing hormone in the hypothalamus and the luteinizing hormone in the pituitary remained unchanged. Serum luteinizing hormone and testosterone levels decreased, but serum follicle-stimulating hormone levels increased. These results suggest that morphine inhibits the hypothalamic-pituitary-gonadal axis and causes a diminution in the number of fertilizations of the partner females.

Introduction:There are two types of phenylalanine, one of the essential amino acids, D-Type and L-type. Phenylalanine in itself has shown no clear analgesic effect in human beings, however, as we reported previously, D-type phenylalanine (DPA) when administered prior to acupuncture analgesia in human beings lengthens the analgesic effects of acupuncture. At this time then, using volunteers in whom acupuncture analgesia failed to raise the pain threshold (PT) we experimentally studied whether or not DPA has any influence.Methods:Subjects were divided into an acupuncture anesthesia effective group (a rise in PT was observed due to acupuncture) and an acpuncture anesthesia ineffective group (no rise in PT). 4.0g. DPA was administered orally in both groups 30 minutes prior to acupuncture anesthesia. For acupuncture anesthesia right and left LI-4 and right and left ST-36 were used with low frequency electric current administered for 50 minutes. For the determination of PT a radiant heat pain meter was used. The PT was measured when DPA was administered, during acupuncture anesthesia and at every 30 minutes for 3 hours after the needles were withdrawn.Results:In the acupuncture anesthesia effective group, a rise in the PT was observed in 4 of the 5 cases and, the rise was much faster than when acupuncture anesthesia was used alone. In the acupuncture anethesia ineffective group, there were cases in which a remarkable rise in PT was observed or in which no rise in the PT occured during acupuncture stimulation but occured after the discontinuation of the acupuncture and some cases in which no rise occured during or after anesthesia.Discussion:1. In the acupuncture anesthesia effective group due to DPA pre-medication, the rate of PT rise quickened.2. After operations the PT rise was lengthened.3. The individuality of the acupuncture effectiveness in human beings was partially eliminated.

Either pethidine HCl (50 mg/kg s.c.) or methadone HCl (8 mg/kg s.c.) produced a prominent decrease in locomotor activity of rats. Pretreatment of rats with p-chlorophenylalanine (p-CPA, 320 mg/kg i.p.) 48 h before the narcotic injection significantly antagonized the activity-decreasing effects of narcotics. When rats pretreated with p-CPA were given 5-hydroxytryptophan (75 mg/kg s.c.) 30 min before narcotic administration, the activity-decreasing response to narcotics was restored. Thus, a decrease in locomotor activity induced in rats by either pethidine or methadone is probably mediated by serotonergic mechanisms.

When (6)-shogaol (0.5 mg/kg, i.v.) was administered to rats, blood pressure showed a tri-phasic response which was comprised of a rapid fall, followed by a rise and a delayed fall. The rapid fall, which followed immediately after injection of (6)-shogaol, disappeared with the use of atropine and vagotomy. The marked rise, which occurred after the rapid fall, was not affected by alpha-adrenoceptor blockades, Ca antagonists and ganglion blockade. However, a combination of alpha-adrenoceptor blockade and Ca antagonist inhibited this pressor response. In hindquarters perfused with a nutrient solution, (6)-shogaol (10(-5) g)-induced peripheral pressor response was also not affected by alpha-adrenoceptor blockades and Ca antagonists, but was inhibited by the combination of an alpha-adrenoceptor blockade and a Ca antagonist. Furthermore, this peripheral pressor response was eliminated by the removal of Ca ion from the perfusate. (6)-Shogaol did not exhibit a pressor response in an artery and a vein of the tail or an artery of the femur perfused with a nutrient solution. (6)-Shogaol-induced peripheral pressor response in hindquarters was markedly potentiated during the perfusion of norepinephrine (5 X 10(-6) g/ml), but this potentiation was prevented by pretreatment with reserpine (5 mg/kg, i.p.). Moreover, repeated injections of (6)-shogaol caused a tachyphylaxis in mesenteric and tail vascular beds and a slight tachyphylaxis in hindquarters.

Summary: The El mouse is an inbred strain developed from ddY mice and is very susceptible to seizure. In El mice, convulsions could be induced by 18 mg/kg of pentylenetetrazol, which is an inert dose in ddY mice. The features of the convulsions were the same as those induced by the tossing-up procedure, a common method to evoke convulsions in El mice. Phenytoin, phenobarbital, valproate sodium, and ethosuximide clearly inhibited pentylenetetrazol-induced convulsions in El mice. These findings suggest that induction of convulsions by pentylenetetrazol in the El mouse is a simple method as compared with induction of convulsions by the tossing-up procedure, and convulsions evoked by this method are a precise experimental model for the study of hereditary epilepsy and for the evaluation of anticonvulsant drugs. RESUMEN El raton El es una cepa natural desarrollada a partir del raton ddY y muy susceptible a crisis. En el raton El, peuden inducirse convulsiones mediante 18 mg/kg de pentilentetrazol, que es una dosis inerte en el raton ddY. Las caracteristicas de las convulsiones fueron las mismas que las inducidas por el procedimiento de lanzamiento hacia arriba del animal que es un metodo habitual de producir convulsiones en el raton El. Fenitoina, fenobarbital, valproato sodico y etoxusimida claramente inhiben las convulsiones inducidas por pentilentetrazol en el raton El. Estos hallazgos sugieren que la induccion de convulsiones por pentilentetrazol en el raton El es un metodo sencillo comparado con la induccion de convulsiones mediante el procedimiento de lanzamiento hacia arriba, y que las convulsiones evocadas por este metodo son un modelo experimental preciso para el estudio de la epilepsia hereditaria y para la evaluacion de las drogas anticonvulsi vantes. ZUSAMMENFASSUNG Die El-Mause sind ein Inzuchtstamm der sich von den ddY-Mausen ableitet und sehr empfanglich fur Anfalle ist. Bei EL-Mausen konnten Konvulsionen durch 18 mg/kg Pentylentetrazol, eine ungefahrliche Dosis fur ddY-Mause, erzeugt werden. Das Aussehen der Krampfe entsprach dem, das durch Hochwerfen, einer ublichen Methode bei EL-Mausen Krampfe hervorzurufen, ausgelost werden konnen. Phenytoin, Phenobarbital, Natrium-Valproat und Ethosuximid inhibierten die Pentylentetrazol-induzierten Krampfe bei EL-Mausen. Diese Befunde deuten darauf hin, das die Induktion von Krampfen durch Pentylentetrazol bei der EL-Maus eine einfache Methode ist, verglichen mit der Induktion von Krampfen durch das Hochwerfen der Tiere und das Konvulsionen, die durch diese Methode hervorgerufen werden, ein gutes experimentelles Modell fur die Untersuchung der hereditaren Epilepsie und fur die Prufung der antikonvulsiven Medikamente darstellen.

Effects of the Japanese Kampo medicine ‘Shosaiko-to-go-keishika-shyakuyaku-to’ (TJ-960), which is a mixture of 9 herbal drugs and is practically equivalent to ‘Saiko-keishi-to’ (SK), on the pentylenetetrazol (PTZ)-induced EEG power spectrum changes were examined. The EEG power spectrum change with 2 PTZ administrations at an 80 min interval was clearly inhibited by oral administration of 1.0 mg/kg of TJ-960. By separate single administrations of the main component herbal drugs, Bupleuri radix, Cinnamomi cortex, Paeoniae radix and Zingiberis rhizoma, only Paeoniae radix showed statistically significant inhibition of PTZ-induced EEG power spectrum changes at a proportional dose of 1.0 mg/kg of TJ-960. The other main component herbal drugs showed no statistically significant inhibitory effect although they had a tendency to inhibit. These findings suggest that the Japanese Kampo medicine, TJ-960 (SK), has an inhibitory effect on PTZ-induced power spectrum changes and one of the component herbal drugs, Paeoniae radix, is the important component drug.

In view of the reduction of side effects as well as the enhancement of anti-tumor activities of anticancer drugs, we have been interested in the combined use of Chinese medicines with them. In the present study, we attempted to examine the effects of Chinese prescription, juzentaihoto (JTX), combined with mitomycin C (MMC). JTX is consisted of Astragali radix, Chinnamomi cortex, Rehmanniae radix, Paeonia radix, Cnidii rhizoma, Atractylodis lanceae rhizoma, Angelicae radix, Ginseng radix, Hoelen and Glycyrrhizae radix. In BDF1-mice which were implanted with P-388 leukemic cells, JTX prolonged significantly the average survival days of MMC-treated group. In tumor-free BDF1-mice, JTX improved the leukopenia and the body weight loss which were caused by MMC. Additionally, JTX delayed the appearance of deaths by lethal dosis of MMC. These results indicate that JTX enhances the anti-tumor activity of MMC and lessens the adverse effects of it. JTX may be useful for patients undertaking MMC treatment.

(6)-Shogaol-induced pressor responses in blood pressure of rats were studied. Intraventricular injection of (6)-shogaol (0.1 to 0.5 microgram) caused a pressor response in a dose-dependent manner. (6)-Shogaol (0.5 mg/kg, i.v.)-induced pressor response was markedly reduced by a spinal destruction to the sacral cord level. However, norepinephrine (10 micrograms/kg, i.v.)-induced pressor response was not affected by the spinal destruction. In rats in which the spinal cord was destroyed to the thoracic cord level, (6)-shogaol-induced pressor response was reduced by hexamethonium (10 mg/kg, i.v.) and phentolamine (10 mg/kg, i.v.), etc. When the spinal cord was destroyed to the sacral cord level, the pressor response was not affected by these blockades. In the hindquarters of rats which were perfused with rats' blood, (6)-shogaol caused two pressor responses on the perfusion pressure. The first pressor response, which was accompanied by a rise in systemic blood pressure, was reduced by hexamethonium but was not entirely eliminated by phentolamine. However, the pressor response disappeared with spinal destruction to the sacral cord level. The second pressor response, which occurred about when the systemic blood pressure regained its original pressure, was not affected by hexamethonium, phentolamine or spinal destruction. Pressor response induced by the injection of (6)-shogaol (10 micrograms) into the perfusion circuit was not affected by phentolamine and spinal destruction. Furthermore, (6)-shogaol-induced peripheral pressor response disappeared with the combined treatment of [D-Arg1, D-Pro2, D-Trp7.9, Leu11]-substance P (0.5 mg/kg, i.v.), phentolamine and the section of the sciatic nerves.

Using Yanagita's activity-level counter, effects of morphine administration upon the spontaneous activities of rats under various conditions were studied. And the following facts were elucidated;1. It was shown numerically that the more the size of the dose was large and the more the duration of morphine repetition was long, the faster and the stronger their spontaneous activities became.2. Such changes of the spontaneous activities of rats due to the repeated administration of morphine can be regarded as one the signs of tolerance.3. The changes of the spontaneous activities of rats or some sorts of tolerance occur as fast as the appearance of physical dependence.4. The mechanisms by which rats become hyperactive by the repeated administration of morphine may be explained chiefly by the development of tolerance to the sedative action of morphine and by the absence of tolerance to the excitatory action of the drug. However, the extraordinary increases recognized by the long term repetition of morphine request us further studies.5. As far as slow morphinization of rats is adopted, the abstinent phenomenon of the morphinized rats is sedation.6. The disappearance of tolerance after the cessation of morphine administration occurs very late, far later than the disappearance of abstinent phenomenon.7. Frequent administrations of nalorphine to the morphinized rats can not shorten the duration of tolerance retention after the cessation of the medication.

Increases both in spontaneous locomotor activity and in body weight were observed after the administration of morphine-HCl (100 mg/kg, i. p.) to tolerant rats. These signs were inhibited by pretreatment of the morphine-tolerant rats with cholinergic antagonists; the inhibition by scopolamine was greater than that by methscopolamine or atropine. These results suggest that both central and peripheral cholinergic mechanisms participate in the increases both in spontaneous locomotor activity and in body weight of tolerant rats after morphine administration.

Effect of Shosaikoto (TJ-9), Hochuekito (TJ-41) and Juzentaihoto (TJ-48) on phagocytic activity of leukocytes in mice was investigated.When TJ-9, TJ-41 or TJ-48 was given to mice either intraperitoneally or orally, all of these Kampo medicines enhanced the phagocytic activity of peritoneal exudate cells (PEC) .Oral administration of TJ-41 or TJ-48 also stimulated the phagocytosis of PEC, spleen cells and bone marrow cells. In contrast TJ-9 enhanced only the activity of PEG.