The Effects Of Chinese Medicine, Guiyuan Tablets On Morphine Tolerance, Withdrawal And Behavioral Sensitization

Repeated administration of opiate drugs induces tolerance and dependence, which are the main reason that limits the clinical use of these drugs in long-term treatment. Although intensively studied, the mechanisms involved in the development of tolerance to and dependence on opiates remain unclear. So the current practices for management of these problems are inadequate. The use of Chinese traditional medicine in the field of drug abuse produces a new method for the prevention and treatment of opiate tolerance and dependence. In this research, we observed the effects of Guiyuan tablets, the composite formula of traditional medicine, on the development and expression of morphine tolerance and dependence. The main results are as follows:1. Effects of Guiyuan tablets on the development and expression of morphine tolerance. The hot plate test was used for assessing analgesia. Chronic administration of morphine decreased the latency and induced the development of tolerance to the analgesic effect of morphine. Acute administration of Guiyuan tablets reversed the tolerance of morphine, and co-administration of Guiyuan tablets with morphine during the induction phase blocked the development ofmorphine tolerance.2.Effects of Guiyuan tablets on morphine physical dependence. Models of morphine-dependent rats and mice were established by dose-increasing administration. After precipitated by naloxone, the abstinent symptoms were observed. The withdrawal syndrome of mice was assessed by recording withdrawal jumps for 15 min and weight loss 1 h after induced by naloxone. Guiyuan tablets dose-dependently reduced vertical jumping and weight loss. Furthermore, co-administration with Guiyuan tablets in the induction phase inhibited the development of morphine dependence in mice. Guiyuan tablets also dose-dependently decreased the global withdrawal symptoms including wet dog shakes, weight loss, teeth chewing, irritating precipitated by naloxone in morphine-dependent rats.3.Effects of Guiyuan tablets on the expression of pCREB in the locus coeruleus (LC) of morphine-withdrawal rats. Many researches showed LC was one of the brain regions that had relation to morphine physical dependence. We observed the expression of pCREB in LC induced by naloxone in morphine-independent mice. The result showed withdrawal increased the extent of pCREB , while co-administration with Guiyuan tablets inhibited the induction. Therefore, the mechanism of effects of Guiyuan tablets on the expression of morphine dependence may be involved of cAMP path.4.Effects of Guiyuan tablets on the development and expression of morphine behavioral sensitization. Locomotor activity was measured every 5 minutes for 1 hour immediately after administration with Guiyuan tablets in mice. Mice were made behavioral sensitization to morphine by subcutaneous injection of 20mg/kg morphine once daily for 7 days, and treatment with the combination of morphine and Guiyuan tablets to investigate the effects of Guiyuan tablets on thesensitization to morphine. The results showed that Guiyuan tablets dose-dependently inhibited the baseline locomotor activity in mice and blocked development and expression of behavioral sensitization to morphine in mice, but did not affect transfer of behavioral sensitization. Guiyuan tablets have inhibitory effects on the central nervous system and suppress the development of morphine addiction behavior. These findings indicate that Guiyuan tablets may be of interferential potential to psychological dependence on morphine in clinic.