RACK1 inhibits morphine re-exposure via inhibition of Src.

Objective: We previously demonstrated that receptor for activated C kinase 1 (RACK1) inhibited phosphorylated extracellular signal-regulated kinase (p-ERK) during morphine reward in mice. In the present study, we examined the role of Src in regulating the inhibition of p-ERK in the brain following RACK1 over-expression during morphine reward.

Methods: Mice were subcutaneously injected with morphine on days 2, 4, 6, and 8 after pre-test (day 1), and saline was delivered the following day. After mice showed place preference, RACK1 over-expression plasmid was administered by intraventricular injection 20 minutes after morphine injection on days 11 and 13. Conditioned place preference (CPP) was measured on days 14, 15, 19, and 20.

Results: Chronic morphine injection increased Src and p-ERK expression in cortex and hippocampus, and mice exhibited increased place preference. Intraventricular administration of RACK1 reduced Src and p-ERK levels in cortex and hippocampus, as well as morphine reward. At 7 days of final RACK1 administration, the effects of RACK1 on Src and p-ERK disappeared, and morphine place preference was restored.

Conclusion: We demonstrated that RACK1 acts on ERK activation via Src in morphine reward in mice.