【作者】 刘艳丽；

【导师】 吴春福； 宫泽辉；

【作者基本信息】 沈阳药科大学 ， 药理学， 2005， 博士

【摘要】 l-四氢巴马汀（l-THP）是中药延胡索中的有效成分，近年来有研究提示l-THP能对抗吗啡依赖和减轻吗啡戒断症状。本课题旨在研究l-THP能否对抗羟考酮依赖及其可能的机理，从以下五个方面着手研究： 1、羟考酮依赖潜能的研究。目前关于羟考酮依赖特性的研究很少，我们采用躯体依赖和精神依赖多种模型考察羟考酮的依赖潜能。用连续递增给药法观察到羟考酮能使小鼠和大鼠形成躯体依赖，纳洛酮催促时产生明显的戒断症状，其依赖潜能与吗啡类似。在精神依赖实验中发现羟考酮能使小鼠自发活动升高，形成行为敏化，使大鼠形成稳定的条件性位置偏爱和自身给药行为。以上结果提示羟考酮具有较强的依赖潜能。在受体水平上，采用分别转染μ、δ、κ三种阿片受体的CHO细胞株，用放射性配体[³H]-Diprenorphine竞争结合实验，观测到羟考酮对三种阿片受体IC₅₀分别是480.3±140.3nmol/L、144.6±36.1nmol/L和361±181.0nmol/L，其亲和力均低于吗啡(吗啡的IC₅₀分别是1.32±1.29nmol/L、27.7±23.5nmol/L和16.9±12.9nmol/L)。此结果提示羟考酮可能对μ、δ、κ三种阿片受体结合没有选择性，可能是阿片受体非选择性激动剂。 2、l-THP拮抗羟考酮依赖的药效学研究。实验结果提示，l-THP能抑制羟考酮依赖小鼠纳洛酮催促时跳跃次数的增加，抑制羟考酮依赖大鼠戒断症状的发生；l-THP（18.75mg/kg，i．g．）不影响小鼠的自发活动，也不能形成敏化，但能抑制羟考酮诱发小鼠行为敏化的形成：l-THP（6.25，12.5，18.75mg/kg，i．g．）能抑制羟考酮诱导小鼠行为敏化的表达，但不能抑制行为敏化的转化：l-THP（20mg/kg，i．g．）能抑制羟考酮引起大鼠稳定的自身给药行为；l-THP（12.5，18.75mg/kg，i．g．）不能形成条件性位置偏爱，但抑制羟考酮引起的大鼠条件性位置偏爱的形成。以上实验结果提示l-THP能拮抗羟考酮引起的大鼠和小鼠躯体依赖和精神依赖。 3、l-THP对抗羟考酮依赖的多巴胺能神经机制研究。应用脑微透析技术结合高效液相—电化学检测系统测定纹状体单胺类神经递质及其代谢产物含量。实验结更多还原

【Abstract】 Recent reports have indicated that l-tetrahydropalmatine （l-THP）, which is an active component of Corydalis maybe have inhibited effects of morphine-induced dependence in rats and mice. The aim of our study is to investigate whether l-THP inhibits oxycodone-induced physical and psychological dependence in mice and rats, and find possible mechanisms of these effects. The results were followed:1. Studies on mechanisms of oxycodone-induced dependence were done. Few reports have been published about the intrinsic pharmacology of oxycodone. In our studies some kinds of oxycodone-induced dependence mode were used. Oxycodone induced physical dependence with naloxone-precipitated withdrawal signs in mice and rats. Locomotor activity was greatly increased and locomotor sensitivity was developed inducded by oxycodone in mice. The conditional place preference and self-administration was developed induced by oxycodone in rats. These results indicated that oxycodone had great potency of dependence in mice and rats. Competitive binding assay was carried on Chinese hamster ovarian cell separately transfeced with μ-,δ-, κ-opioid receptor to determine the receptor selectivity of oxycodone with non-selective antagonist ³H-diprenorphine. The results showed that the affinities of oxycodone to three types opioid receptors were similar, the number of IC₅₀ separately were 480.3±140.3, 144.7±36.1, 361±181.1 nmol/L, that of morphine are 1.32±1.29, 27.7±23.5, 16.9±12.9 nmol/L. These results indicate that the affinities of oxycodone to three types of opioid receptors are weaker than that of morphine, and oxycodone may be non-selective agonist.2. Studies on effects of l-THP on oxycodone-induced dependence in mice and rats. The results showed that l-THP per set didn’t have potency of dependence, but could inhibit更多还原