| Chronic exposure to opiate makes the body develop the dependence on and tolerance to opiate. The study on mechanism of opiate dependence and tolerance remains a challenge for all the scientists so far.The cycle nonapeptide oxytocin (OT) is synthesized predominantly within the magnocellular neurons of the hypothalamic supraoptic (SON) and paraventricular nuclei (PVN), and is secreted from the axon terminals of these neurons in the posterior pituitary gland. Lately, many studies have indicated that OT has some effects on the processes of learning, memory and drug addiction. OT may inhibit the development of tolerance to and dependence on morphine, heroin, ~3-endophine and enkephalin. Naloxone-precipitated morphine withdrawal syndrome is also attenuated by OT. Heroin self-administration is decreased by OT in heroin-tolerant rats. Intracerebroventricular (ICV) and intracerebral (injected into the basal forebrain structures) administration of an OT-receptor antagonist potentiates the development of morphine tolerance and dependence, indicating central OT can inhibit the development of morphine tolerance and dependence. Acute opioid agonists inhibit the electrical activity of magnocellular OT neurons and its secretion. Chronic morphine treatment can reduce OT levels in the brain. Withdrawal induced by administration of the opiate antagonist naloxone elicits a prolonged hyper-excitation of OT neurons leading to hyper-secretion of OT. Opioid inhibits the release of OT so as to attenuate the inhibition of OT on development of opiate dependence and tolerance. It is important to clarify the mechanism of opiate inhibition on OT neurons in the SON and OT secretion. This will be helpful to design some new drug against the opiate6dependence and tolerance.The G-protein-gated inwardly rectifying K+ channels (GIRK), a member of the family of inwardly rectifying K+ channels, can be activated by directly binding of Gfry. It has been found that the GIRK channels were coupled to numerous neurotransmitter receptors and GIRK channels are important physiological tools to regulate excitability in brain and heart by neurotransmitters. GIRK channels play an important role in the modulation of not only the heart rate but also neurotransmitter release and neuronal excitability. The p.-opioid receptor can activate GIRK channels expressed in vitro in the presence of agonist, and ~t-opioid receptor agonist can activate GIRK channel via the ji-opioid receptor in vivo. This raises the possibility that GIRK channel is a mediator of opioid action in the SON. It is possible that GIRK channels can mediate the inhibition of morphine on OT synthesis and release from the SON. However, little is known about expression of GIRK channels in this area.Chronic morphine treatment not only elicits many neurotransmitters and neuromodulators to alter in central nervous system, but also leads to some changes of cellular signal transduction and gene expression. Previous research has failed to identify consistent changes in the number of opiate receptors, or alterations in their affinity for opiate ligands under condition of opiate addiction. It remains unclear whether long-term activation of opioid receptor can result in changes of the expression of its direct effectors GIRK channels.In this study the changes of oxytocin content and mRNA expression in some nuclei were investigated in morphine dependent rats using radioimmunoassay (RIA) and in situ hybridization (ISH). The effects of chronic morphine on the OT release from the SON organotypic slice in vitro, which had no connection with other nuclei of the brain, was studied in order to exclude the influences of noradrenegic and glutamatergic afferent inputs from other nuclei. Thereafter, we examined the distribution of the GIRKI-4 mRNAs in the SON and identified whether or not the neurons that synthesized the GIRXI -4 in the SON were oxytocinergic neurons using double-labeled methods of immunohistochemistry and in situ hybridization. Finally,7we observed the changes in t...
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