• 생약학회지
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• 제16권1호
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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.

• Biomolecules & Therapeutics
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• 제2권4호
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• pp.316-321
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• 1994

This study was undertaken to estimate whether nalbuphine, a mixed agonist/antagonist opioid analgesic produced psychic dependence. Moreover, the physical dependence liability of nalbuphine was compared with that of morphine after 7 days administrations of the drugs in mice and rats, and the effects of ginseng total saponin (GTS) on the development of physical dependence on nalbuphine were also studied. Nalbuphine did not produce psychic dependence. However, various abstinence signs precipitated by naloxone were observed in nalbuphine-dependent mice and rats. As the nature of the dependence syndrome produced by nalbuphine 30 mg/kg under these conditions seems similar to that induced by morphine 10 mg/kg, it is clear that nalbuphine possesses the substantial abuse potential. Therefore, nalbuphine may be needed to initiate more stringent controls for the prevention of nalbuphine abuse. On the other hand, GTS inhibited the development of physical dependence on nalbuphine and reduced the contents of dopamine and its metabolite in the brains of mice. Accordingly, results of this study suggest that the inhibitory effects of GTS on the development of physical dependence on nalbuphine may involve dopaminergic mechanism. GTS may be useful for the therapy of physical dependence on nalbuphine.

• The Korean Journal of Physiology and Pharmacology
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• 제16권6호
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• pp.379-386
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• 2012

The purpose of this study was to evaluate whether berberine (BER) administration could attenuate depression- and anxiety-like behaviors and increase corticotrophin-releasing factor (CRF) and tyrosine hydroxylase (TH) expression following chronic morphine withdrawal in rats. Male rats were exposed to chronic, intermittent, escalating morphine (10~50 mg/kg) for 10 days. After the last morphine injection, depression- and anxiety-like beahvior associated with morphine discontinuation persisted for at least three days during withdrawal without any change in ambulatory activity. Daily BER administration significantly decreased immobility in the forced swimming test and increased open-arm exploration in the elevated plus maze test. BER administration also significantly blocked the increase in hypothalamic CRF expression and TH expression in the locus coeruleus (LC) and the decrease in hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression. Taken together, these findings demonstrated that BER administration significantly reduced morphine withdrawal-associated behaviors following discontinuation of repeated morphine administration in rats, possibly through modulation of hypothalamic CRF and the central noradrenergic system. BER may be a useful agent for treating or alleviating complex withdrawal symptoms and preventing morphine use relapses.

• The Korean Journal of Physiology and Pharmacology
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• 제4권4호
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• pp.291-299
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• 2000

Morphine or butorphanol was continuously infused into cerebroventricle (i.c.v.) with the rate of $26\;nmol/{\mu}l/h$ for 3 days, and the withdrawal from opioid was rendered 7 hrs after the stopping of infusion. The expression of physical dependence produced by these opioids was evaluated by measuring the naloxone-precipitated withdrawal signs. The withdrawal signs produced in animals dependent on butorphanol (kappa opioid receptor agonist) were similar to those of morphine (mu opioid receptor agonist). Besides the behavioral modifications, opioid withdrawal affected G protein expression in the central nervous system. The G-protein ${\alpha}-subunit$ has been implicated in opioid tolerance and withdrawal. The effects of continuous infusion of morphine or butorphanol on the modulation of G protein ${\alpha}-subunit$ mRNA were investigated by using in situ hybridization study. In situ hybridization showed that the levels of $G\;{\alpha}s$ and $G\;{\alpha}i$ were changed during opioid withdrawal. Specifically, the level of $G\;{\alpha}s$ mRNA was decreased in the cortex and cerebellar granule layer during the morphine and butorphanol withdrawal. The level of $G\;{\alpha}i$ mRNA was decreased in the dentate gyrus and cerebellar granule layer during the morphine withdrawal. However, the level of $G\;{\alpha}i$ mRNA was significantly elevated during the butorphanol withdrawal. These results suggest that region-specific changes of G protein ${\alpha}-subunit$ mRNA were involved in the withdrawal from morphine and butorphanol.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.50-62
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• 1994

Opium, morphine and rotated natural and synthetic opiates have been used since antiquity, and to the present, for the relief of moderate and severe pain. Morphine and pharmacologically related drugs, however, produced an array of undesired or dangerous side effect that limit their use as analgesics. Prominent among the limiting side effects are constipation, respiratory depression, release of prolactin, and liability for the production of drug dependence. It was our aim to develop, if possible, a drug or class of drugs with analgesic activity similar to that of morphine, but without the serious side effects associated with morphine. Our overall strategy was to take advantage of advancing knowledge concerning multiple types of opioid receptors, to develop ligands selective for the delta type receptors, to determine whether delta receptor agonists offer advantages over mu agonists, then to design compounds with pharmacokinetic properties compatible with practical therapeutic application. All but the last of these objectives have been realized.

• 약학회지
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• 제29권4호
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• pp.188-192
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• 1985

김등은 한국산 인삼의 부탄올분획이 마우스의 모르핀 내성 및 의존성 형성을 억제하였고 rat의 모르핀에 의한 내성 형성 및 dopamine 수용체 초과민성 형성을 억제한다고 보고 하엿다. 저자들은 Takagi가 보고한 인삼의 중추신경계를 억제시키는 protopanaxadiol (PD) 분획과 중추신경계를 흥분시키는 protopanaxatriol (PT) 분획을 사용하여 모르핀의 내성형성에 미치는 활성 분획을 추적할 목적으로 진통작용에 대한 내성 형성 억제 체온 상승 또는 강하 억제작용 체중감소 억제작용 등을 실험하였다.

• The Korean Journal of Physiology and Pharmacology
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• 제1권6호
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• pp.691-697
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• 1997

The mechanisms underlying opiate tolerance and dependence are not fully understood. We used human neuroblastoma SH-SY5Y cells as a model system for studying effects of morphine tolerance and withdrawal on c-myc induction and cAMP levels. It has been reported that regulation of c-fos by acute and chronic morphine withdrawal is mediated through alterations in CREB transcription factor. In this study, we examined the effects of morphine tolerance on c-myc expression and cAMP concentrations. The activation of opiate receptors by an acute morphine administration resulted in an increase in c-myc mRNA and a decrease in cAMP concentrations in a dose-dependent manner $(5,\;10,\;15,\;and\;20\;{\mu}M)$. On the other hand, the chronic treatment of morphine $(10\;{\mu}M\;for\;six\;days)$ did not induce the elevated expression of c-myc mRNA. The c-myc expression was slightly inhibited in comparison with that of the acute morphine response. However, cAMP concentrations were increased with regard to morphine withdrawal response. These results suggest that the alterations in c-myc expression might imply a significant opiate regulation relating to morphine tolerance. This observation differs from increased expression of c-fos via regulation of cAMP pathway.

• Archives of Pharmacal Research
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• 제28권9호
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• pp.995-1001
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• 2005

Morphine-induced analgesia has been shown to be antagonized by ginseng total saponins (GTS), which also inhibit the development of analgesic tolerance to and physical dependence on morphine. GTS is involved in both of these processes by inhibiting morphine-6-dehydrogenase, which catalyzes the synthesis of morphinone from morphine, and by increasing the level of hepatic glutathione, which participates in the toxicity response. Thus, the dual actions of ginseng are associated with the detoxification of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contractions in guinea pig ileum (I-L-receptors) and mouse vas deferens $(\delta-receptors)$ are not mediated through opioid receptors, suggesting the involvement of non-opioid mechanisms. GTS also attenuates hyperactivity, reverse tolerance (behavioral sensitization), and conditioned place preference induced by psychotropic agents, such as methamphetamine, cocaine, and morphine. These effects of GTS may be attributed to complex pharmacological actions between dopamine receptors and a serotonergic/adenosine $A_{2A}1\delta-opioid$ receptor complex. Ginsenosides also attenuate the morphine-induced cAMP signaling pathway. Together, the results suggest that GTS may be useful in the prevention and therapy of the behavioral side effects induced by psychotropic agents.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2005년도 추계학술대회
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• pp.49-66
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• 2005

Panax ginseng has been useful for the treatment of diverse disease in oriental countries for thousands of years. In addition, a folk medicine prescribed by seven herbal drugs including Panax ginseng has been antinarcotics in the treatment of morphine-dependent patients. Many articles have been reported on these works. Therefore, we review the protective effects of Panax ginseng on the neurotoxicity induced by abuse drugs. Ginseng total saponins (GTS) extracted and isolated by Panax ginseng antagonized Morphine-induced analgesia, and inhibited the development of analgesic tolerance to and physical dependence on morphine. GTS inhibited morphine-6 dehydrogenase, which catalyzes production of mophinone from morphine, and increased hepatic glutathione level responsible to toxicity. Therefore, we hypothesized that these dual actions of ginseng can be associated with the detoxication of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contraction in guinea pig ileum ($\mu$-receptors) and mouse vas deferens($\delta$-receptors) were not mediated through opioid receptors, suggesting non-opioid mechanisms. On the hand, antagonism of U-50,488H ($\kappa$-agonist)-induced antinociception is mediated by serotonergic mechanisms. GTS also inhibited hyperactivity, reverse tolerance (sensitization) and conditioned place preference-induced by psychostimulants such as methamphetamine, cocaine and morphine. On the other hand, GTS reduced the dopamine levels induced by methamphetamine. Moreover, GTS blocked the development of dopamine receptor activation, showing antidopaminergic effect. We suggest that GTS Prevent the methamphetamine-induced striatal dopaminergic neurotoxicity. In addition, Ginsenoside also attenuates morphine-induced cAMP signaling pathway. These results suggested that GTS might be useful for the therapy of the adverse actions of drugs with abuse liability.

• 고려인삼학회:학술대회논문집
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• 고려인삼학회 1998년도 Advances in Ginseng Research - Proceedings of the 7th International Symposium on Ginseng -
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• pp.168-173
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• 1998

A single administration of cocaine (CO), morphine (MOR) and methamphetamine (MA) showed hyperactivity in mice. Ginseng total saponin (GTS), ginsenosides Rbl and Rgl inhibited the hyperactivity induced by the drugs. The repeated administration of CO, MOR and MA showed the development of psychological dependence showing a.: the development of conditioned place preference (CPP) in mice and the development of dopamine (DA) receptor supersensitivity showing as sensitization of the drugs. GTS and Rgl inhibited the development of not only psychological dependence but also of DA receptor supersensitivity induced by CO and MA Rbl prevented also the development of psychological dependence and DA receptor supersensitivity induced by CO and MA but not by MOR. These results suggest that the development psychological dependence induced by the drugs is closely related with the development of DA receptor supersensitivity since both phenomena were inhibited by them. Apomorphine induced climbing behavior was also inhibited by G75 but not by both of Rbl and Rgl, indicating that GTS modulate dopaminergic action at both of pre and postsynaptic sites, but both of Rbl and Rgl , only at the presynaptic site. These results suggest that active components acting at the postsynaptic site exist in GTS. In this study, it was found that GTS, ginsenosides Rbl and Rgl inhibited tyrosine hydroxylase (TH) and these components exerted inhibitory effects on both Cal' currents and $\Delta$ Cm in rat adrenal chromaffin cells. These results suggest that G75 and ginsenosides regulate catecholamine synthesis and secretion. Meanwhile, it has been demonstrated that Rbl, at high doses has more powerful inhibition of cartecholamine secretion at the presynaptic site than Rbl. Therefore, it was presumed that inhibition of morphine induced psychological dependence by Rgl, but not by Rbl results from differences in the extent of this inhibitory action on dopaminergic synthesis and secretion.