Study On The Mechanisms Of Phosphorylation In Morphine Tolerance And Dependence

Opioids, such as morphine and heroin, are extensively used to relieve pain. However, long-term use of these drugs results in the development of tolerance and dependence, and withdrawal symptoms are severe. Tolerance and dependence not only limit the therapeutic use of opioids, but also result in tragic consequences for those who abuse these drugs. The aim of this study was to explore cellular and molecular mechanisms of morphine tolerance and dependence in order to seek new ways to prevent and treat opioid tolerance and dependence. By establishing a model of morphine tolerance and dependence in mice and morphine dependence-like model in SH-SY5Y neuroblastoma cells, we examined changes in some cellular messenger concentrations and protein kinase activities and the regulation of some key enzymes such as AC, NOS, sGC, PDE in the pathway of signal transduction and phosphorylation of c-Fos by PKA and PKC in brain regions isolated from morphine-(?)lerant and -dependent mice and in SH-SY5Y cells. The major results were described as follows:1. A model of morphine tolerance and dependence in mice was established. Morphine of increased doses was subcutaneously administered to mice twice a day for 7 days. On day 4, there was no apparent morphine analgesic effect. On day 7 the morphine-dependent mice were challenged by s.c. naloxone within 2hr after the last injection of morphine, and the withdrawal syndrome which manifested as jumping, weight loss, diarrhea, ptosis, rearing, etc. could be observed.2. Effect of morphine tolerance and dependence on cAMP, cGMP and inositol phosphates contents in the brain regions of mice. In morphine-tolerant and -dependent mice, cAMP contents in several brain regions (striatum, hippocampus and cerebral cortex) were significantly higher than those of control, and cGMP contents inthese brain regions were significantly lower than those of control. In morphine-tolerant and -dependent mice, IP and IP3 contents in striatum, IP in cerebral cortex and total inositol phosphates in striatum and cerebral cortex were markedly higher than those of control, especially in striatum and cortex. These findings suggest that in...