• 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.

• 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.

• Korean Journal of Pharmacognosy
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• v.16 no.1
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• pp.31-35
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• 1985

Intraperitoneal administration of ginseng butanol fraction(GBF) to chronic morphinization in male Sprague-Dawley rats inhibited the development of tolerance to the analgesic effect and hyperthermic action of morphine. Rats were rendered tolerant to morphine by subcutaneous multiple morphine injections for a period of 8 days. The development of tolerance was evidenced by the decreased analgesic response to morphine and inhibition of tolerance by the greater analgesic response. Concomitant administration of morphine with GBF blocked the tolerance to the hyperthermic effect of morphine as evidenced by elevation of body temperature by morphine. Dopamine receptor sensitivity was enhanced in morphine tolerant rats as measured by apomorphine induced in spontaneous motor activity. GBF administration also blocked dopamine receptor supersensitivity induced by chronic morphinization.

• 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.

• The Korean Journal of Pain
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• v.14 no.2
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• pp.225-230
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• 2001

Background: Opioids such as morphine are widely used in the treatment for pain, but chronic treatment with morphine can be complicated by the development of tolerance. The mechnisms of tolerance were still not completely understood, but recently it has been reported that NOS inhibitors can prevent development of morphine tolerance in animals. The present study accessed the possible role of supraspinal NO on antinociceptive effect of morphine in morphine tolerance using a highly specific inhibitor of the neuronal isoform of NOS, 1-(2-trifluoromethylphenyl) imidazole (TRIM). Methods: Thirty two male SD rats (300 g) were prepared with intracerebroventricular (icv) and IV cannulae. We administrated IV morphine, 3 mg/kg, daily for 4 days, resulting in tolerance. On the fifth day, a challenge dose of morphine, 3 mg/kg, was administered following pretreatment with icv TRIM, $10{\mu}g$. We also evaluated the antinociceptive effect of icv TRIM alone and the effect on a single dose of morphine (3 mg/kg) in morphine nave rats. Antinociception from morphine was determined by response to intraplantar injection of 5% formalin $100{\mu}l$ was qualified as the number of flinches in the first 0-10 min (first phase), 10-40 min Phase IIa, and 40-60 min (Phase IIb). Results: Pretreatment with icv TRIM significantly enhanced the antinociceptive effects of systemically administered morphine in morphine tolerant rats. The antinociceptive effect of morphine in opioid nave rats was also significantly increased by pretreatment with icv TRIM. Conclusions: Our results further support the hypothesis that supraspinal NO modulates morphine-sensitive nociceptive process in morphine tolerance due to chronic intravenous administration.

• Archives of Pharmacal Research
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• v.26 no.12
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• pp.1074-1078
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• 2003

The effects of glycine on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice was examined. A single administration of morphine (10 mg/kg, s.c.) induced hyperactivity as measured in mice. The morphine-induced hyperactivity was inhibited by pretreatment with glycine (100, 200 and 400 mg/kg, i.p.). In addition, it was found repeated administration of morphine (10 mg/kg, s.c.) to mice daily for 6 days caused an increase in motor activity which could be induced by a subsequent morphine dose, an effect known as reverse tolerance or sensitization. Glycine (100, 200 and 400 rng/kg, i.p.) also inhibited morphine-induced reverse tolerance. Mice that had received 7 daily repeated administrations of morphine also developed postsynaptic dopamine receptor supersensitivity, as shown by enhanced ambulatory activity after administration of apomorphine (2 mg/kg, s.c.). Glycine inhibited the development of postsynaptic dopamine receptor supersensitivity induced by repeated administration of morphine. It is suggested that the inhibitory effects of glycine might be mediated by dopaminergic (DAergic) transmission. Accordingly, the inhibition by glycine of the morphine-induced hyperactivity, reverse tolerance and dopamine receptor supersensitivity suggests that glycine might be useful for the treatment of morphine addiction.

• The Korean Journal of Pain
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• v.37 no.3
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• pp.233-246
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• 2024

Background: Ferrostatin-1 and liproxstatin-1, both ferroptosis inhibitors, protect cells. Liproxstatin-1 decreases morphine tolerance. Yet, ferrostatin-1's effect on morphine tolerance remains unexplored. This study aimed to evaluate the influence of ferrostatin-1 on the advancement of morphine tolerance and understand the underlying mechanisms in male rats. Methods: This experiment involved 36 adult male Wistar albino rats with an average weight ranging from 220 to 260 g. These rats were categorized into six groups: Control, single dose ferrostatin-1, single dose morphine, single dose ferrostatin-1 + morphine, morphine tolerance (twice daily for five days), and ferrostatin-1 + morphine tolerance (twice daily for five days). The antinociceptive action was evaluated using both the hot plate and tail-flick tests. After completing the analgesic tests, tissue samples were gathered from the dorsal root ganglia (DRG) for subsequent analysis. The levels of glutathione, glutathione peroxidase 4 (GPX4), and nuclear factor erythroid 2-related factor 2 (Nrf2), along with the measurements of total oxidant status (TOS) and total antioxidant status (TAS), were assessed in the tissues of the DRG. Results: After tolerance development, the administration of ferrostatin-1 resulted in a significant decrease in morphine tolerance (P < 0.001). Additionally, ferrostatin-1 treatment led to elevated levels of glutathione, GPX4, Nrf2, and TOS (P < 0.001), while simultaneously causing a decrease in TAS levels (P < 0.001). Conclusions: The study found that ferrostatin-1 can reduce morphine tolerance by suppressing ferroptosis and reducing oxidative stress in DRG neurons, suggesting it as a potential therapy for preventing morphine tolerance.

• 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.

• 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.

• Archives of Pharmacal Research
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• v.13 no.1
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• pp.38-42
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• 1990

The present study was undertaken to determine the inhibitory effects of cholane compounds, unsodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on the development of morphine-induced tolerance and physical dependence, and also to determine the hepatic glutathione contents. UDCA and CDCA inhibited the development of morphine-induced tolerance and physical dependence significantly. UDCA inhibited the hepatic glutathione decrease induced by morphine multiple injections, while this effect was not observed in CDCA treated mice. It was throught that the inhibitory effects of hepatic glutathione decrease in morphine-treated mice by UDCA and CDCA showed a tendency of inhibitory effects of development of morphine tolerance and dependence.