Spatial transcriptomics reveals distinct cell type dynamics following opioid dependence in mice with the common human variant in the μ-opioid receptor, A118G.

Opioid Use Disorder (OUD) is a multifaceted neuropsychiatric disease that can arise from genetic, environmental, and neurobiological factors. The A118G single nucleotide polymorphism (rs1799971) encodes an N40D variant in the μ-opioid receptor (MOR) and is linked to increased risk of opioid and other drug dependencies, though its exact mechanism remains unknown. With the ongoing opioid crisis driving record overdose deaths, understanding how this variant influences addiction risk could open new therapeutic avenues. We applied a systematic, cross-modality platform to assess cell dynamics using spatial transcriptomics and uncover not only distinct spatially resolved transcriptome changes in opioid exposed mice, but also changes dependent on the variant. Collectively, our findings suggest that genetic risk for opioid dependence at the locus may be reflected more strongly in glial cell adaptations rather than neuronal dysfunction, emphasizing the importance of oligodendrocyte-mediated neuroimmune interactions in opioid dependence.