Agmatine On Morphine Dependent Regulation Of Rat Hippocampal Neurogenesis And Its Possible Mechanism

Previous studies showed agmatine, an endogenous imidazoline I receptor ligand, prevent morphine dependence, but the mechanism remains unclear. The neurogenesis has long been the focus of research about drug dependence for its involvement in psychological dependence. It was well known the hippocampus might play an important role in this process. Present study, therefore, the effect of agmatine on neurogenesis on morphine dependence and the possible mechanism was evaluated.Firstly, we made animal model in morphine dependence by 12d progressively increased administration method. Agmatine were co-administrated with morphine 10mg/kg/d or administrated single. Naloxone withdrawal syndrome results indicated that agmatine inhibit morphine dependence. By immunohistochemistry assay it was found that BrdU-positive cells number in hippocampus of morhine dependence rats were down-regulated by 23%±4% but agmatine single administration could not change BrdU-positive cells number in rat hippocampal. In addition, agmatine inhibited the decreases of both phosphorylations of CREB and ERK, and the expression of c-fos that induced by morphine dependence. Secondly, we separated neural progenitor cells (NPCs) from neonatal rats hippocampus and studied the effect of proliferation on cells by morphine and agmatine. It was found that morphine (1~100μmol.L-1) inhibit NPCs proliferation by 48h culture and agmatine increase proliferation respectively, agmatine improve inhibition effect of morphine on NPCs. The effect of morphine and agmatine can be inhibited by naloxone and efaxoran respectively in culture cells. At the same time, we observed the effect of morphine and agmatine on CHO cells that contains CHO-μ and CHO-I, and co-expressed CHO-μ/I1 cells. By CCK-8 kit and 3H- thymidine incorporate assay it was found that the effects are paralleled with its in NPCs. So it indicated that morphine effect on mu-opioids receptor to inhibit cells proliferation and agmatine's increases proliferation may be related with imidazoline I receptor. The mechanism that neuroprotective effect of agmatine on morphine dependence may be related with modulation cAMP/MAPK—CREB signal transduct pathway and result in inhibitory of BDNF releasing from interneuron of local region such as hippocampus.