• YAKHAK HOEJI
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• v.46 no.4
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• pp.276-282
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• 2002

Morphine has been used widely on the treatment of many types of chronic pain. However the development of tolerance to 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, k-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 days. 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 tolerance to morphine 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 20 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 (100:1) significantly attenuated the development of morphine tolerance and dependence. These results suggest that the co-administration of nalbuphine with morphine in chronic morphine treatment can be one of therapies to reduce the development of dependence on morphine.

• Toxicological Research
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• v.19 no.4
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• pp.311-314
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• 2003

This study was performed to investigate the effects of glycine on the development of tolerance to and physical dependence on morphine. Repeated administration of morphine (10 mg/kg) developed tolerance and physical dependence. Glycine (100, 200 and 400 mg/kg) was administered intraperitoneally (i.p.) to mice for 7 days prior to the morphine injection. Analgesic effects were estimated by the tail flick methods. The inhibitory degree of the development of morphine-induced analgsic tolerance by i.p. administration of glycine was evidenced by the increase in analgesic response to morphine. Glycine inhibited the development of tolerance to morphine. In addition, we separately measured jumping response as the naloxone-precipitated withdrawal sign in mice that had received the same morphine. Glycine reduced the number of jumping behaviors in morphine dependent mice. These results suggest that glycine might be useful the prevention or treatment of morphine tolerance and physical dependence.

• Korean Journal of Pharmacognosy
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• v.17 no.2
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• pp.139-147
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• 1986

Ginseng saponins(GS), protopanaxadiol saponins(PD) and protopanaxatriol saponins (PT) were tested for the inhibition of the development of morphine tolerance and dependence antagonism of morphine analgesia and the loss of morphine tolerance and dependence in mice The results were as follows: 1. Inhibition of the development of morphine tolerance and dependence. 2. Antagonism of morphine analgesia. 3. Increase in the loss of morphine tolerance and dependence. Antagonism of morphine by ginseng saponins and its reversal by L-DOPA and 5-HTP suggest some possibility that catecholamines and serotonin levels might be associated with the results.

• Biomolecules & Therapeutics
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• v.4 no.3
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• pp.232-238
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• 1996

The physical dependence potency of DA-5018, a non-narcotic analgesic agent, was tested in mice dosed with 0.5 and 4 mg/kg/day for 2 months and daily increasing doses of 1, 2, 4, 6, 8 and 10 mg/kg over 10 days. Physical dependence was assessed taking natural withdrawal induced morphine-type abstinence (jumping, falling, biting or backward locomotion, rearing etc.) as well as barbiturates-type abstinence (body weight reduction, convulsion, ataxia etc.) into consideration. The results were compared with those after the same daily increasing doses of morphine. DA-5018 did not show evidence of physical dependence liability or abuse potential as measured by morphine-type or barbiturate-type abstinence signs following daily increasing or 2-month repeated administration. On the other hand, daily increasing doses of morphine produced physical dependence and the dependent state disappeared about 6 hours after the start of withdrawal signs. In the single dose suppression test, a single dose of morphine completely suppressed natural withdrawal signs that appeared in morphine-dependent animals. Therefore, these results indicate that DA-5018 does not have abuse potential and physical dependence liability.

• Proceedings of the Ginseng society Conference
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• 1987.06a
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• pp.38-46
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• 1987

The present study was undertaken to determine the inhibitory effects of orally administered ginseng saponins (GS), protopanaxadiol saponins(PD) and protopanaxatriol saponins(PT) on the development of morphine induced tolerance and physical dependence in mice, and to determine the increases in the loss of morphine tolerance and dependence. The study also sought to determine the hepatic glutathione contents, which are closely related to the degree of detoxication of morphinone, a novel metabolite of morphine, and the effects of ginseng saponins on morphine 6-dehydrogenase. The results of the present study showed that GS, PD and PT administered orally inhibited the development of morphine-induced tolerance and dependence. GS, PD and PT, however, increased the loss of morphine tolerance and dependence. GS, PD and PT inhibited the reduction of hepatic glutathione concentration in mice treated chronically with morphine, and the activity of morphine 6-dehydrogenase. So we hypothesized that these results were partially due to the dual action of the test drugs, the inhibition of morphine production and the activation in morphine-glutathione conjugation due to the increased glutathione level for detoxication.

• Journal of Ginseng Research
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• v.40 no.4
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• pp.445-452
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• 2016

Background: Red ginseng and ginsenosides have shown plethoric effects against various ailments. However, little is known regarding the effect of red ginseng on morphine-induced dependence and tolerance. We therefore investigated the effect of red ginseng extract (RGE) and biotransformed ginsenosides Rh2, Rg3, and compound K on morphine-induced dependence in mice and rats. Methods: While mice were pretreated with RGE and then morphine was injected intraperitoneally, rats were infused with ginsenosides and morphine intracranially for 7 days. Naloxone-induced morphine withdrawal syndrome was estimated and conditioned place preference test was performed for physical and psychological dependence, respectively. Western blotting was used to measure protein expressions. Results: Whereas RGE inhibited the number of naloxone-precipitated jumps and reduced conditioned place preference score, it restored the level of glutathione in mice. Likewise, ginsenosides Rh2, Rg3, and compound K attenuated morphine-dependent behavioral patterns such as teeth chattering, grooming, wet-dog shake, and escape behavior in rats. Moreover, activated N-methyl-D-aspartate acid receptor subunit 1 and extracellular signal-regulated kinase in the frontal cortex of rats, and cultured cortical neurons from mice were downregulated by ginsenosides Rh2, Rg3, and compound K despite their differential effects. Conclusion: RGE and biotransformed ginsenosides could be considered as potential therapeutic agents against morphine-induced dependence.

• 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.16 no.1
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• pp.13-17
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• 1992

The present experiments were performed to investigate the effects of the ginseng total saponin on the development of physical dependence on morphine via intracerebroventricular (i.c.v) route. Morphine (10 $\mu\textrm{g}$/${mu}ell$/hr) was continuously infused via osmotic minipumps into lateral cerebral ventricle of male Sprague Dawley rats for 7 days. Concurrent ginseng total saponin (100, 200 $\mu\textrm{g}$/10${mu}ell$/hr) was infused intraperitoneally (i.p) via osmotic pumps for 7 days. Treatment with ginseng total saponin (200$\mu\textrm{g}$/10${mu}ell$/hr) significantly diminished jumping, teeth chattering, hypothermia and weight loss precipitated by naloxone, compared with those animals received only morphine infusion. These results suggest that ginseng total saponin has central effect on the inhibition of physical dependence on morphine, as systemic ginseng total saponin inhibits the development of physical dependence in rats infused with morphine intracerebroventricularly.

• 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.

• Archives of Pharmacal Research
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• v.10 no.3
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• pp.188-192
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• 1987

The present study was undertaken to determine the inhibitory effects of orally administered ginseng saponins (GS), protopanaxadiol saponins (PD), protopanaxatriol saponins (PT) and ginseng ether fraction (GE) on the development of morphine induced tolerance and physical dependence in mice and also to determine the hepatic glutathione contents. GS, PD and PT inhibited significantly the development of morphine induced tolerance and physical dependence, but GE was effective only on the inhibition of the development of morphine induced physical dependence. GS, PD, PT and GE also inhibited the hepatic glutathione level decrease induced by morphine multiple injections.