Potential role of ecto-5'-nucleotidase in morphine-induced uridine release and neurobehavioral changes

摘要

OBJECTIVE There is growing evidence that uridine may act as an endogenous neuromodulator with a potential signaling role in the central nervous system in addition to its function in pyrimidine metabolism.We previously found that acute morphine treatment significantly increased uridine release in the dorsal striatum of mice,while the mechanism involved in morphine-induced uridine release and the role of uridine in morphine-induced neurobehavioral changes have not been understood.METHODS Uridine release in the dorsal striatum of mice was assessed by in vivo microdialysis coupled with high performance liquid chromatography(HPLC) after morphine treatment.Western blotting and immunofluorescence were used to evaluate the expression of uridine-related proteins.Morphine-induced neurobehavioral changes were assessed by locomotor activity,behavioral sensitization and conditioned place preference(CPP)test.The expression of NT5E,an extracellular enzyme involved in formation of nucleosides,including uridine,was specifically knocked down in the dorsal striatum of mice using adeno-associated virus(AAV)-mediated short hairpin RNA(shRNA).RESULTS Both acute and chronic morphine administration significantly increased uridine release in the dorsal striatum,and this was associated with upregulation of NT5E but not other uridine-related proteins.Inhibition of NT5E with APCP or shRNA markedly inhibited morphine-induced uridine release in the dorsal striatum and related neurobehavioral changes,including hyperlocomotor activity,behavioral sensitization and CPP.CONCLUSION The present study increases our understanding of the contribution of NT5E in regulating morphine-induced neurobehavioral changes,at least as related to uridine,and suggests that NT5E may be a novel therapeutic target to manage morphine abuse.