| Physical dependence ,psychological dependence and drug tolerance to the drug-addicts are three important pharmacological characteristics of opioids, the mechanism of which is always the question for discussion. Along with the discovery of opioid receptors and endogenous ligards for opioid receptors, the investigation of the mechanism comes to a new phase. During the opioid dependence , a series of regulation systems have been changed in recent research, such as neuronal system.,intercellar information systems, nucleotide metabolism The main purpose of the research is to study the effect on Amino Acid metablism and to discover the possible target gene during the heroin dependence . glutamine synthetase(GS) is not only a critical enzyme for Amino Acid metablism in liver, but also a key enzyme for Glutamate-Glutamine cycle in CNS(Central nervous system). The effects of GS on the mechanism of heroin dependence have not be reported in the world, so it is a valuable alternative way to investigate the mechanism of opioid dependence through Amino Acid mechanism.We designed the rat model of heroin dependence and withdrawal to study the mechanism of opioid dependence and withdrawal. By analysis of activity of GS and concentration of GS mRNA in defferent tissues we demonstrate that whether heroin affects the metabolism of Amino Acid and whether GS exhibit a correlation with the development of opioids dependence. The results shows:1: Glutamate is the major excitatory neurotransmitter in the mammalian brain and glutamate uptake is essential for the normal function of glutamatergic synapses. Clearance of synaptic glutamate by glial cells is required for the normal function of excitatory synapses and for prevention of neurotoxicity. It is well established in some studies that glutamate transporters play a regulatory role in glutamate clearance. Whereas some recent researches ( Iftach shaked, 2002 ) demostrate that GS activity significantly influences the uptake of glutamate by the neural retina ( neurogliocyte subtype) and suggest that this enzyme may represent an important target for neuroprotective strategies . In our studies GS activity of cerebrum parietal lobe decreases significantly in both d3th heroin treatment group and d9th heroin treatment group.Interstingly,GS activity is much lower in d3th heroin withdrawal group,and keeping decreasing in d8th heroin withdrawal group.GS RT-PCR analyses revealed that the declince tendence of GS RT-PCR products was not appropriated to that of GS activity in cerebrum parietal lobe during the herion dependence period.It could be deduced that the effect of herion on GS activity happened not only in gene transcription level but also in protein regulation level. our results suggest that glutamine synthetase(GS),a glial-specific enzyme that amidates glutamate to glutamine affects the uptake of glutamate and contribute to the high level concentrations of intercellular glutamate during the heroin dependence. The effects on amino acid metabolism by GS on body still remain going on long after the effect of heroin dispeared. GS activity in brain stem also be decreased in d3th heroin withdrawal group,compared with control group,and remain normal level in d8th herion withdrawal group. We think GS in brain stem may take part in the development of heroin withdrawal symptoms.2. GS play a key role in amino acid metablism in liver. It was established that μ recepters distributed extensively in the liver which was considered the material –energy metablism center. In our studies GS activity in liver shows an increased tendency in heroin dependent group. The transcription of mRNA of liver GS was markedly improved to ,In heroin dependence period Glutamine was synthesized in liver by use of ammonia and contriute to attenuate the degradation of muscle protein when catambolism enhanced on body.Whereas GS activity in muscle increased obviously in d3th heroin withdrawal group,it could be concluded that catablism of protein in muscle tissue be strengthened in early h... |
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