A primary behavioral pathology in drug addiction is the overpowering motivational strength and decreased ability to control the desire to obtain drugs, which shows some variation between different individuals. Here, using a morphine-induced conditioned place preference (CPP) model with footshock, we found that mice exhibited significant individual differences in morphine-induced addiction. Despite the consequences of footshock, a small percentage of mice (24%) still showed stable morphine preference, demonstrating resistant to punishment. The majority of mice (76%) were relatively sensitive to punishment and showed termination of morphine preference. As a region of advanced cognitive function in the mammalian brain, the medial prefrontal cortex (mPFC) is involved in regulating drug-induced addictive behaviors. We found that activating the pyramidal neurons in the prelimbic cortex (PrL) could effectively reverse morphine-induced CPP in resistant mice, and inhibiting pyramidal neurons in the PrL could promote morphine-induced CPP in sensitive mice. To further explore the differences between resistant and sensitive mice, we analyzed the differences in gene expression in their PrL regions through RNA-seq analysis. The results showed that compared to sensitive mice, the significantly downregulated differentially expressed genes (DEGs), such as Panx2, Tcf7l2, Htr2c, Htr5a, Orai3, Slc24a4 and Cacnb2, in resistant mice were mainly involved in synaptic formation and neurodevelopment. We speculated that there may be defects in the neuronal system of resistant mice, and caused they are more prone to morphine-induced CPP. These findings are likely to contribute to research in gene therapy, and they may also serve as potential therapeutic targets for drug addiction.