| BackgroundThe protracted withdrawal symptoms of opiate dependence is included in the syndrome after drug abstinence in TCM theory. The protracted withdrawal symptoms is the series of sustained symptoms following the acute abstinence syndrome, such as tireness, impatience, pain round the body, persistent insomnia, depression, desire for drug, anxiety, and so on. It is one of the factors of relapse. At present, western medicine treats protracted withdrawal symptoms with opioid agents,α2 receptor agonist or sedative hypnotic therapy and so on. These therapies possess a rapid and exact efficacy, with many side effects, and easily to cause an addiction as well. TCM treatment for protracted withdrawal symptoms is safe therapy with few side effects, and no addiction itself. TCM has the characteristic of strengthening healthy qi to eliminate pathogens, whole regulation, dealing with both root cause and symptoms, a low toxicity and no addiction. At present there are various prescription preparations of Chinese medicine treatment for opiate dependence which have been approved production for the clinical use, but these preparations are mostly used for the acute withdrawal symptoms, and no for protracted withdrawal symptoms. Based on the previous pharmacological studies and clinical efficacy assessments, Qingfeng capsule, a new prescription preparations, was showed obviously sedative and hypnotic actions, analgesic and prevention of addiction. It could treat the protracted withdrawal symptoms, such as impatience, insomnia, desire for medicine, anxiety, pain round the body. The preliminary researches on Qingfeng capsules were mostly focused on pharmacological and clinical effects. The clinical effects of Qingfeng for protracted withdrawal symptoms is obvious and the researches in pharmacology have revealed parts of the function mechanism, but the mechanism of Qingfeng based on TCM theory have not been involved .ObjectiveThe aim of this study is to explore and develop TCM theory on protracted withdrawal symptoms of opiate dependence, and to perfect mechanism of Qingfeng capsules.Methods1. Theoretical researches: (1) Arranging literature of TCM to know how TCM understand protracted withdrawal symptoms of opiate dependence, and how to carry out treatment and the key of therapy. (2) Analyzing Qingfeng capsules' components of Chinese drug with Chinese medicine theory to understand how the various components of drug work, and the efficacy of Qingfeng capsules.2. Experimental researches: Establishing the repeated morphine-dependent and withdrawal animal model, to investigate the effects of Qingfeng capsules to each indicator related that had been select for the experiment, and explaining the efficacy of Qingfeng capsules with related theories: (1) The model of morphine-dependent rats was established by dose-increasing administration. The rats were given morphine from 10mg/kg (sc) to 80mg/kg (sc) each time for 5 days, the rats of control group were given the same volume of saline. Withdrawal syndrome was precipitated by naloxone (2.0mg/kg) 2 hour after the last time morphine was given. The process above was repeated after stopped morphine administration for 14 days. Qingfeng capsules was given(ig) for 5 days. The bodyweight and food intake of the rats were observed and the erythrocyte count, hemoglobin level and blood viscosity in rats were examined. (2) The model of morphine-dependent mice was established by dose-increasing administration. The rats were given morphine from 25mg/kg (sc) to 150mg/kg (sc) each time for 5 days, the rats in control group were given the same volume of saline. Withdrawal syndrome was precipitated by naloxone (4.0mg/kg) 2 hour after the last time morphine was given. The process above was repeated two times after stopped morphine administration for 7 days. Qingfeng capsules was given(ig) for 5 days. The locomotor activity and swimming time of the mice were observed. (3) Establishing the model and giving Qingfeng capsules by the methods above, to observe c-fos gene expression in the blood of the mice. (4) The Experiment results were analyzed by SPSS11.5 statistical software, the method was single-factor analysis of variance.Results1. Theoretical researches(1) The protracted withdrawal symptoms was named as symptoms after abstinence in TCM theory. TCM considers that after long-time use of opioid, Qi-Blood and body fluid are seriously depletive in the body. After withdrawal from opioid, a series of withdrawal symptoms appear due to the damage to the viscera in the body. The pathogenesis of the symptoms after abstinence is due to withdrawal of pathogenic factor, Qi-Blood and body fluid are depletive, yin and yang become estranged, and viscera is damaged in the body. The characteristics of symptoms after abstinence are stagnant toxin and lack of healthy qi. There are four common types of protracted withdrawal symptoms: stagnant toxin and deficiency of qi and blood, stagnant toxin and deficiency of qi and yin, stagnant toxin and flaming of fire from yin deficiency, stagnant toxin and deficiency of yin and yang. About treatment for protracted withdrawal symptoms, according to the deficiency of healthy energy and sthenia of evil in the body of addicts, strengthening healthy qi to eliminate pathogens is the main principle in TCM treatment and rehabilitation on addicts. Strengthening healthy qi and body resistance is mainly replenishing qi and blood, replenishing qi and yin, nourishing yin and fluid and replenishing yin and yang. Eliminating pathogenic factors is mainly from diuresis, heat-clearing and detoxifying, purgation of smoke toxicity, emesis of smoke toxicity, and so on. After abstinence of drug, it's important to replenish qi and blood, restore function of the spleen and stomach, and consolidate the acquired constitution.(2) Qingfeng capsules are composed of Caulis Sinomenii, Ginseng and other Chinese drugs. Caulis Sinomenii is bitter in flavour and flat in property, the channel-tropism of medicine is mostly liver and spleen, and Caulis Sinomenii possesses the efficacy of dispelling wind, dredging collaterals, analgesia and inducing urination. Sinomenine is a main active ingredients from Caulis Sinomenii, has a similar chemical structure with morphine, but they are different in the molecular structure and the groups arrangement, so that Sinomenine possesses anti-morphine without the addictive effect. Ginseng is sweet in flavour and slight bitter in property, the channel-tropism of medicine is mostly spleen, lung and heart. Ginseng possesses the efficacy of replenishing primordial qi, restoring pulse and collapse syndrome, strengthening spleen and lung, promoting body fluid, tranquilization, replenishing qi to strengthen blood, yang, body fluid and yin. It could be applied to deficiency syndrome of acute withdrawal symptoms or protracted withdrawal symptoms. Ginsenosides are main ingredients from ginseng, possess the effects of resisting morphine addiction. Ginseng also possesses the effects of sedative and anticonvulsant, and it can increase intestinal transport functions, improve the gastrointestinal symptoms. Base on TCM theory Caulis Sinomenii is mainly used for removing stasis and eliminating pathogenic factor in the body, ginseng mainly for strengthening body resistance. The mechanism of the prescription is just according to the principle of treatment and rehabilitation after withdrawal in TCM theory.2. Experimental researches(1) The effects of the Qingfeng capsules on food intake and bodyweight in the morphine-dependent rats: After given Qingfeng capsules (ig), the rats in each groups had increased in food intake to a certain extent. Trough analyzing the increases of food intake with statistical methods, we found that the variance was irregular(P = 0.000), and Dunnett's T3 showed that there was no significant difference in the different groups. The bodyweight of the rats were increased after administration, through analyzing the increases on third day and sixth day with statistical methods, we found that there were significant differences in the groups(F = 16.930, P = 0.000 and F = 13.673, P = 0.000). The bodyweight increases on third day and sixth day were both less in morphine model group than control group(P = 0.000), and the index was more in Qingfeng capsule high dose group than morphine model group (P= 0.004, P= 0.002). The bodyweight increases on third day had on significant difference between Qingfeng capsule middle dose group and morphine model group(P= 0.061). On third day and sixth day the bodyweight increases both had no significant difference between Qingfeng capsule low dose group and morphine model group (P= 0.216, P= 0.336). The index on third day and sixth day both had no significant difference between Shiquandabuwan group and morphine model group ( P= 0.883, P= 0.968).(2) The effects of Qingfeng capsules on blood viscosity in the morphine-dependent rats: the results of whole blood viscosity showed that in shear rate of 1s-1, there were significant differences between the groups(F= 2.558, P= 0.042), the whole blood viscosity were higher in morphine model group than that in control group(P= 0.005), the index in Qingfeng capsule high, middle and low dose group were all lower than that in morphine model group(P= 0.005, P= 0.016, P= 0.021), and there were no significant difference between Shiquandabuwan group and morphine model group(P= 0.061). In shear rate of 5s-1, there were significant differences in the groups(F= 2.702, P= 0.034), the whole blood viscosity were higher in morphine model group than blank control group(P= 0.010), the index in Qingfeng capsule high, middle and low dose group were all lower than morphine model group(P=0.006, P= 0.026, P= 0.005), and there were no significant difference between Shiquandabuwan group and morphine model group(P= 0.149). In shear rate of 30s-1 and 150s-1 there were no significant difference between the groups(F= 1.624, P= 0.176 and F= 1.390, P= 0.249).The results of plasma viscosity showed that there were significant differences between the groups(F= 3.165, P= 0.017), the index were higher in morphine model group than that in control group(P= 0.032), and were lower in Qingfeng capsule high dose group than in morphine model group(P= 0.029). There were no significant difference between morphine model group and Qingfeng capsule middle or low dose group, or Shiquandabuwan group(P= 0.824, P= 0.194, P= 0.428).(3) The effects of Qingfeng capsules on erythrocyte count, hemoglobin level and hematocrit in the morphine-dependent rats: The results showed that in comparison with the above indices there were no significant difference between the groups(F= 1.604, P= 0.186; F= 1.179, P= 0.340 and F= 1.088, P= 0.385).(4) The effects of Qingfeng capsules on locomotor activities in the morphine-dependent mice: The numbers of locomotor activity changed after the mice were given drug. Through analyzing the numbers of increase with statistical methods, we found that there were significant differences between the groups(F= 3.994, P= 0.005), the numbers increased were lower in morphine model group than that in control group(P= 0.041). The locomotor activity were higher in Qingfeng capsule high, middle and low dose group than that in morphine model group(P= 0.000, P= 0.001, P= 0.008). There were no significant difference between morphine model group and Shiquandabuwan group(P= 0.182).(5) The effects of Qingfeng capsules on swimming time in the morphine-dependent mice: The swimming time after the mice were given Qingfeng capsules were analyzed with statistical methods. The variance was irregular(P= 0.008), and Dunnett's T3 showed that there was no significant difference along the groups.(6) The effects of Qingfeng capsules on c-fos gene expression of blood in the morphine-dependent mice: Observing each blood smear from left to right for three positions under the microscope, to count the numbers of positive cells for the three positions and get a meanvalue number. Trough analyzing the meanvalue numbers of all blood smear with statistical methods, we found that there were significant differences between the groups(F= 4.346, P= 0.003). The number were higher in morphine model group than in control group (P= 0.016), and were higher in Qingfeng capsule high, middle and low dose group than that in morphine model group(P= 0.000, P= 0.005, P= 0.018). There were no significant difference between morphine model group and Shiquandabuwan group(P= 0.163).Conclusion1. The present study showed that Qingfeng capsules could increase the body-weight and food intake in repeated morphine-dependence and withdrawal rats. Based on TCM theory, food intake and bodyweight is a reflection on the functions of the spleen and stomach, and the results of the experiment suggested that Qingfeng capsules has increased the spleen and stomach function so that promoted digestion and absorption of food and strengthened Qi and blood in the body. TCM theory considers that Qi work to keep blood moving in veins and collaterals, the deficiency of Qi would cause blood stasis. After repeated morphine-dependence and withdrawal, the primordial qi of rats were damaged. Because of remaining pathogenic factor in the body, it leaded to a deficiency of Qi and blood stasis. Qingfeng capsules could reduce the whole blood viscosity and plasma viscosity of the rats, it suggest that the prescription preparation possesses the actions of replenishing qi, activating blood circulation and removing stasis and pathogenic factor. Erythrocyte count and hemoglobin level are designed to reflect the function of blood, but the results wasn't statistically significant, the impact of the medicine to them would need further to study.2. Qi possesses the actions of promoting, warming, consolidation, defense, gasification and so on. Blood possesses the actions of nourishing viscera, collaterals and organization, and so on. When the body is hurt, it would cause the deficiency of Qi and blood, and lead to a deficiency of the body function and decreases of vitality and movement, even drowsiness. In the study, after repeated morphine-dependence and withdrawal, the mice showed the number of locomotor activity reduced obviously. Qingfeng capsules could increase the number locomotor activity of mice, it suggest that the preparation possessed the actions of strengthening body resistance, replenishing Qi and blood, and promote vitality of the body. Swimming time of the mice was designed to reflect the function of anti-fatigue and tolerance, but the results wasn't statistically significant, the reason need further to study.3. After repeated morphine-dependence and withdrawal, mice showed a more active c-fos gene expression in blood than that in normal group. The c-fos gene expression of mice were low after treatment with Qingfeng capsules. Many researches showed that blood stasis is connected with c-fos gene expression in the body. The treatment with Qingfeng capsules could improve the blood stasis, it also corrected the c-fos gene expression. Considering with all above, we come to a conclusion that blood stasis is connected with c-fos gene expression. Qingfeng capsules could regulate the c-fos gene expression in morphine-dependent mice, at the same time it reflected macroscopically on the body that it improve the symptom of blood stasis and qi stagnation. Qingfeng capsules possess the efficacy of promoting qi and activating blood circulation, this is one of the reasons why it could be used to treat protracted withdrawal symptoms. From the experiment of c-fos gene expression, we got a research of microcosmic level basing on the original macro observation, it perfected our researches further more, and revealed the connection between Qi deficiency, blood stasis syndrome and levels of gene changes from macro to micro, so as to provide molecular biology researches for diagnosis and treatment in TCM.In conclusion, through theoretical and experimental researches above, we can know that Qingfeng capsules possess the efficacy of removing stasis, replenishing Qi and blood, strengthening and restoring effects and eliminating pathogenic factor in the body, and could treat protracted withdrawal syndrome.
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