Transcriptional Reprogramming of GPCR Signaling Pathways in the Frontal Cortex of Morphine Dependent Mice

Repeated morphine administration for managing persistent pain frequently induces both physical and psychological dependence, accompanied by alterations in cortical gene expression. To elucidate the molecular underpinnings of morphine dependence, gene expression in the frontal cortex of mice subjected to acute and chronic morphine treatment was profiled using microarray analysis and validated by semi-quantitative PCR. Genes including Drd2, Adora2a, Olfr767, Egr2, Gng7, and Gpr6 were upregulated following both acute and chronic morphine treatment. Gene ontology analysis revealed significant enrichment of differentially expressed genes in membrane components, GPCR signaling pathways, and neurological system processes, indicating integrated alterations in receptor-mediated signaling and downstream transcriptional regulation. Consistent with this, selective phosphorylation of CREB was observed during naloxone-precipitated withdrawal, highlighting CREB-dependent transcription as a key molecular correlate of cortical neuroadaptation. Behavioral assays confirmed robust physical and psychological dependence, supporting the functional relevance of these molecular changes. Collectively, these findings identify a GPCR-centered molecular framework in which coordinated regulation and functional interaction of receptors such as DRD2 and ADORA2A, along with associated signaling components, contribute to morphine-induced neuroplasticity and dependence. These insights may provide a foundation for the development of targeted therapeutic strategies to mitigate opioid dependence.