[논문]Inhibitory Action of the Natural Product AP1700 on the Withdrawal Syndrome of Nalbuphine

Kang, Jong-Seok; Lee, Hun-Kyu; Kim, Dong-Hyun; Yoo, Hwan-Soo; Jang, So-Yong; Oh, Sei-Kwan

Inhibitory Action of the Natural Product AP1700 on the Withdrawal Syndrome of Nalbuphine 원문보기

The journal of applied pharmacology : the official journal of the Korean Society of Applied Pharmacology, v.13 no.1, 2005년, pp.13 - 19

Kang, Jong-Seok (Graduate School of Sports Science, Korea National Sports University) , Lee, Hun-Kyu (Division of Drug Development, Aperio) , Kim, Dong-Hyun (Graduate School of Pharmacy, Chungbuk National University) , Yoo, Hwan-Soo (Graduate School of Pharmacy, Chungbuk National University) , Jang, So-Yong (Department of Neuroscience, School of Medicine, Ewha University) , Oh, Sei-Kwan (Department of Neuroscience, School of Medicine, Ewha University)

Abstract ▼ AI-Helper

The study was undertaken to determine the antagonism of the AP1700 on the development of nalbuphine-induced tolerance and physical dependence. AP1700 is an oriental drug preparationcomposed of 5 natural products and is known to have antinarcotic action with an oral dose of 250 mg/kg in rats. AP1700 significantly inhibits the development of antinarcotic action with an oral dose of 250 mg/kg in rats. AP1700 significantly inhibits the development of nalbuphine-induced physical dependence but does not the tolerance. Mitogen-activated protein kinase, which include extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) play critical roles in cell growth and survival and drug abuse. The level of pCREB was elevated in the hippocampus by the chronic treatment with nalbuphine, however, the elevation of pCREB was not inhibited by the AP1700 co-treatment. Interestingly, the level of pERK was decreased in the co-treatment with nalbuphine and AP1700 on the cortex and striatum. However, the level of nNOS and NR1 was not modulated by the treatment with nalbuphine or AP1700 on the cortex, hippocampus and striatum in the rat brain. These results suggest that the AP1700 could be used to ameliorate the nalbuphine withdrawal symptoms.

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가설 설정

Western blot analysis of protein levels suggests that signal transduction system was not solely attributable to the nalbuphine-induced withdrawal syndrome. We hypothesize that the inhibitory effects of AP1700 on nalbuphine- induced physical dependence are closely related to the modulation of CREB (cyclic AMP response element-binding) protein expression.

제안 방법

Additional groups of rat that had received the same nalbuphine and AP1700 as described in the development of nalbuphine tolerance were used in this experiment. The inhibition of naloxone-induced withdrawal syndrome in nalbuphine-dependent rat was estimated by the observation of the withdrawal syndrome by naloxone 10 ㎎/㎏ (i.
Rats were received nalbuphine (10 ㎎/㎏, i.p.) and/or AP1700 (250 ㎎/㎏, p.o.) for 6 days, and were challenged with naloxone (10 ㎎/㎏, i.p.) 24h after the final injection of nalbuphine. Numbers denote the number of rats showing positive signs over the total number of rats tested for 30 min after injection of naloxone.
AP1700 250 ㎎/㎏ were administered orally to rat Ihr prior to the injection of nalbuphine. The test of nalbuphine analgesia was estimated at 0, 30, 60, 90 minutes for 6days by tail flick methods (n=10). The inhibitory effects of AP1700 on the development of nalbuphine-induced tolerance were shown on day 1 (A), day 3 (B), and day 5 (C).
This study was undertaken to determine the antagonism of nalbuphine analgesia by AP1700, the inhibitory effects of AP1700 on the development of nalbuphine tolerance and physical dependence in rats, and the hepatic glutathione contents which are closely related to the degree of detoxification of mor- phinone, a novel metabolite of morphine (Nagamatsu et W., 1983). Also, we determined the inhibitory effect of AP1700 on the modulation of MAPK, NMDA receptor (NR1 subunit), nNOS expression in the rat brain regions.

대상 데이터

Rats (Sprague-Dawley, male) weighing 250-280g in a group of 10, were used in all experiments. The AP1700 is composed of 5 natural products (Sulfur precipitatum, Aconiti Tuber, Atractyloids Rhizoma Alba, cinnamon, Lonicerae Flos) was dissolved in distilled water and administered orally.

데이터처리

The data were expressed as mean + S.E. The differences in the means for different responses in different treatment groups were analyzed by the Student, s t-test.

성능/효과

In our experimental results, the level of pCREB was not significantly modulated by the co-treatment with nalbuphine and AP1700 although the level was decreased than that of API700 alone. Furthermore the level of NR1 and nNOS was not elevated by the treatment with nalbuphine.

후속연구

, 2004). However, it needs some more experiment to explain the correlation with antagonism of dependence and pERK suppression. It could be presumed that AP1700 ameliorated the drug abuse to inhibit the psychological rewarding via downregulation of pERK expression as well as inhibit the physical dependence.

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