The Influence Of Agmatine On The Adaptation Of The NMDA Receptor Action System In Morphine Dependence

It has been proved that agmatine can enhance morphine analgesia, inhibit tolerance to and dependence on morphine. Besides its activation of imidazoline receptors, the action mechanisms of agmatine might be associated with the blocking of the NMDA receptors. The objective of the present study is to observe the influence of agmatine on the adaptation of NMDA receptor action system in morphine pretreatment.A morphine dependence model of rats was established by repeated administration of morphine with an ascending dose. In the experiment model, agmatine was proved to inhibit the development of morphine dependence in a dose-dependent manner, which was consistent with the previous results reported by our laboratory. It was proved by the method of ELISA that the rabbit anti-agmatine polyclonal antibody we prepared had enough efficacy and specificity to be used in experiments. Using the immunofluorescence double labelling method it was found that agmatine and NMDA receptors were co-distributed in neurons in some brain regions which were closely related to opioid dependence, including the pre-front cortex (PFC) and the hippocampus. Using the methods of immunohistochemistry and western blotting, we found that chronic morphine pretreatment induced some significantly different changes in the expression level of NR1 and NR2B sub-units of NMDA receptors in hippocampus and nucleus accumbens (NAc). Agmatine co-administered with morphine could reverse the changes as mentioned above induced by morphine pretreatment. These results suggest that the inhibitory effects of agmatine on opioid dependence might be related to its reversing the changes of the NMDA receptor expression level and constitution induced by chronic opioid pretreatment. On the other hand, by the method of microdialysis in conscious rats and a synaptosome model, we found that the amount of Glu in microdialysis liquid was markedly increased in hippocampus and NAc during withdrawal induced by naloxone challenge, which might be associated with the increase in the amount of release of Glu from synaptosome and...