• Archives of Pharmacal Research
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• v.29 no.8
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• pp.677-684
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• 2006

Morphine has been used widely on the treatment of many types of chronic pain. However the development of tolerance to and dependence on morphine by repeat application is a major problem in pain therapy. The purpose of the present study was to investigate whether combined administration of nalbuphine with morphine affects the development of tolerance to and dependence on morphine. We hypothesize that the use of nalbuphine, ${\kappa}-agonist$ may prove to be useful adjunct therapy to prevent morphine-induced undesirable effects in the management of some forms of chronic pain. Morphine (10 mg/kg) was injected to rats intraperitoneally for 5 day. The variable dose of nalbuphine (0.1, 1.0 and 5.0 mg/kg) was administered (i.p.) in combination with morphine injection. The development of morphine tolerance was assessed by measuring the antinociceptive effect with the Randall-Selitto apparatus. The development of dependence on morphine was determined by the scoring the precipitated withdrawal signs for 30 min after injection of naloxone (10 mg/kg, i.p.). Nalbuphine did not attenuate antinociceptive effect of morphine in rats. Interestingly, combined administration of morphine with nalbuphine (10:1) significantly attenuated the development of dependence on morphine. The elevation of $[^3H]MK-801$ binding in frontal cortex, dentate gyrus, and cerebellum after chronic morphine infusion was suppressed by the coadministration of nalbuphine. In addition, the elevation of NR1 expression by morphine was decreased by the coadministration of nalbuphine in rat cortex. These results suggest that the coadministration of nalbuphine with morphine in chronic pain treatment can be one of therapies to reduce the development of tolerance to and dependence on morphine.

• Korean Journal of Pharmacognosy
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• v.20 no.2
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• pp.123-127
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• 1989

The effects of ginsenosides on the development of morphine induced tolerance and physical dependence were investigated. $Rb_1,\;Rb_2,\;Rg_1\;and\;Re$ inhibited significantly the development of morphine induced tolerance but $Rb_1\;and\;Rg_1$ showed significant inhibitory effect on the naloxone induced withdrawal jumping response. Ginsenosides inhibited the body weight decrease in physically dependent mice during multiple injection of morphine.

• YAKHAK HOEJI
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• v.29 no.1
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• pp.27-31
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• 1985

The administraction of ginseng butanol fraction(GBF) inhibited the development of tolerance to and physical dependence on morphine induced by morphine multiple injections in mice. Each group of mice was injected with morphine hydrochloride (40mg/kg s.c.) three times at 8 hr intervals for a period of 6 days. GBF (25, 50, 100, 200mg/kg) was injected (i.p.) to mice 1hr prior to the third morphine injection daily. Inhibition of morphine tolerance by GBF was evidenced by the increase in analgesic response to morphine hydrochloride (10mg/kg) as estimated by the tail flick method and the reduction in morphine dependence was estimated by the decreased number of the naloxone induced withdrawal jumping mice. Further evidenced that GBF reduced the development of morphine dependence was indicated by the fact that GBF decreased the loss in body weight.

• Journal of Ginseng Research
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• v.13 no.1
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• pp.8-13
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• 1989

The effects of orally administered ginseng leaf saponins(GLS) on the analgesic action of morphine, the development of morphine induced tolerance and physical dependence, and the hepatic flutathione contents in mice were investigated. GLS antagonized the analgesic action of morphine and inhibited the development of morphine induced tolerance and physical dependence. It also inhibited the decrease in hepatic glutathione level induced by multiple injections of morphine.

• Proceedings of the Ginseng society Conference
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• 1990.06a
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• pp.36-44
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• 1990

The analgesic effect of morphine was antagonized and the development of tolerance was suppressed by the modification of the neurologic function in the animals treated with ginseng saponins. The activation of the spinal descending inhibitory systems as well as the supraspinal structures by the administration of morphine was inhibited in the animals treated with ginseng saponins intracerebrally or intrathecally The development of morphine tolerance and dependence, and the abrupt expression of naloxone induced abstinence syndrome were also inhibited by ginsenoside Kbl , Rba, Rgl and Re. These results suggest that ginsenoside Kbl, Rba, Rgl and Re are the bioactive components of panax ginseng on the inhibition of the development of morphine tolerance and dependence, and the inhibition of abrupt abstinence syndrome. In addition, further research on the minor components of Panax ginseng should be investigated. A single or daily treatment with ginseng saponins did not induce any appreciable changes in the brain level of monoamines at the various time intervals and at the various day intervals, respectively The inhibitory or facilitated effects of ginseng saponins on electrically evoked contractions in guinea pig ileum (U-receptor) and mouse was definers (5·receptor) were not mediated through opioid receptors. The antagonism of a x receptor agonist, U-, iO.488H was also not mediated through opioid receptors in the animals treated with ginseng saponins, bolt mediated through serotonergic mechanisms. Ginseng saponins inhibited morphine S-dehydrogenase that catalyzed the production of morphine from morphine, and increased hepatic glutathione contents for the detoxification of morphine. This result suggests that the dual action of the above plays an important role in the inhibition of the development of morphine tolerance and dependence.

• Journal of Ginseng Research
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• v.23 no.4
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• pp.239-246
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• 1999

The analgesic effect of ginsenosides or morphine was determined following intrathecal (i.t.) administration in rat tail-flick test. The effects of intrathecal co-administration of ginsenosides with morphine on the development of opioid tolerance and dependence were also examined using rat tail-flick test and naloxone-pre-cipitated withdrawal, respectively. Administration of ginsenosides (i.t.) produced a weak antinociception in a dose-dependent manner. Administration of morphine (i.t.) also produced antinociception in a dose-dependent manner. The $ED_50$ was $1.20\;{\mu}g\;(1.14\~1.29\;{\mu}g)$. However, the acute co-administration of $200{\mu}g$ ginsenosides with 0.1-1.0${\mu}g$ morphine did not show additive effect on morphine induced analgesia in rat tail-flick test. I.t. co-administration of 200 ${\mu}g$ ginsenosides with 10 ${\mu}g$ morphine for 7 days inhibited development of tolerance induced by 10 ${\mu}g$ morphine in rat tail-flick test, although i.t. co-administration of 50 or 100 ${\mu}g$ ginsenosides with morphine was without effect. I.t. co-administration of 200 ${\mu}g$ ginsenosides for 7 days also partially attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. In conclusion, these results suggest that i.t. administered ginsenosides produce a weak antinociception in rat tail-flick test and also prevent opioid tolerance and attenuate opioid dependence in chronic treatment with morphine at the spinal sites.

• Journal of Ginseng Research
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• v.14 no.2
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• pp.178-186
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• 1990

The analgesic effect of morphine was antagonized and the development of tolerance was suppressed by the modification of the neurologic function in the animals treated with ginseng saponins The activation of the spinal descending inhibitory systems as well as the supraspinal structures by the administration of morphine was inhibited in the animals treated with ginseng saponine intracerebrally or intrathecally. The development of morphine tolerance and dependence, and the abrupt expression of naloxone inducted abstinence syndrom were also inhibited by ginsenoside Rb1, Rb2, Rg1 and Re. These results suggest that ginsenoside Rbl, Hbs, Rgl and Re are the bioactive components of panax ginseng on the inhibition of the development of morphine tolerance and dependence, and the inhibition of abrupt abstinence sindrome. In addition, further research on the minor components of Pnnnxkinsenl should be investigated. A single or daily treatment with ginseng saponins did not induce any appreciable changes in the brain in level of monoamines at the variolls time intervals and at the various day intervals, respectively. The inhibitory or facilitated effects of ginseng saponins on electrically evoked contractions in guinea pig ileum ($\mu$-receptor) and mouse vats deferens ($\delta$-receptor) were not mediated through opioid receptors. The antagonism of a $\chi$ receptor agonist, U-50, 488H was also not mediated through opioid receptors in the animals treated with ginseng saponins, but mediated through serotonergic mechanisms. Ginseng saponins inhibited morphine 6-dehydrogenase which catalyzed the production of morphinone from morphine, and increased hepatic glutathione contents for the detoxication of morphinone. This result suggests that the dual action of the above plays an important role in the inhibition of the development of morphine tolerance and dependence.

• Korean Journal of Child Studies
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• v.28 no.1
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• pp.205-216
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• 2007

An internet addiction measure(Park et al., 2001) and an asocial behavior measure(K. J. Lee, 1997) were administered to 232 6th-grade students. Statistical analyses were by mean-difference scores and t-test. Results showed that all aspects of internet addiction(preoccupation, compulsive use, relapse, tolerance/dependence and impediments in daily life) were related to both the inner asocial behaviors of depression, social withdrawal and over-anxiety and the external asocial behaviors of aggressiveness, delinquency and hyperactivity. The only exception was that tolerance/dependence was not related to delinquency. Boys addicted to the internet were more socially withdrawn, aggressive, delinquent and hyperactive than girls. From the results, it can be suggested that internet education should be carried out from the elementary educational level.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.04a
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• pp.304-304
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• 1994

The possible mechanisms of ginseng saponins on the inhibition of development of morphine tolerance and physical dependence were investigated in the aspects of morphine metabolism by morphine 6-dehydrogenase. Administration of morphine causes a reduction of non-protein sulfhydryl contents in liver, because morphinone is metabolized from morphine by morphine 6-dehydrogenase conjugates with sulfhydryl compounds. However, ginseng saponins inhibited the activity of morphine 6-dehydrogenase which catalized the production of morphinone from morphine. In addition, ginseng' saponins inhibited the reduction of non-protein sulfhydryl levels by Increasing the level of hepatic glutathione. These results suggest that the dual action of the above plays an important role in the inhibition of development of morphine tolerance and physical dependence. On the other hand, it was observed that less polar components of ginseng saponins with parent structures were more active components in vitro.

• Korean Journal of Pharmacognosy
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• v.25 no.2
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• pp.160-166
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• 1994

The possible mechanisms of ginseng saponins on the inhibition of the development of morphine tolerance and physical dependence were investigated in the aspects of morphine metabolism by morphine 6-dehydrogenase. The administration of morphine causes a reduction of non-protein sulfhydryl contents in the liver, because morphinone metabolized from morphine by morphine 6-dehydrogenase conjugates with sulfhydryl compounds. However, ginseng saponins inhibited the activity of morphine 6-dehydrogenase which catalyzed the production of morphinone from morphine. In addition, ginseng saponins inhibited the reduction of non-protein sulfhydryl levels by increasing the level of hepatic glutathione. These results suggest that the dual action of the above plays an important role in the inhibition of the development of morphine tolerance and physical dependence. On the other hand, it was observed that less polar components of ginseng saponins with parent structures were more active components in vitro.