Spatial transcriptomics reveals distinct cell type dynamics following opioid dependence in female mice with the common human μ-opioid receptor variant Oprm1 A118G.

Opioid Use Disorder (OUD) is a complex neuropsychiatric condition shaped by multiple factors including genetics. The A118G single-nucleotide polymorphism (rs1799971) in the µ-opioid receptor gene (OPRM1) has been associated with heightened risk for opioid and other substance dependencies, but the molecular basis of this effect remains unclear. Importantly, mice with the orthologous SNP, Oprm1 A112G, recapitulate many of the divergent behavioral responses to opioids documented in humans with the same variant. To probe how these variants influence opioid dependence at a cellular and molecular level, we performed single-nucleus spatial transcriptomic analyses of cell-type composition and cell-state/transcriptional programs in Oprm1 A112G mice with and without morphine dependence. A key discovery from our study is that opioid-induced changes in cell type transcriptomic states varied markedly by genotype. Specifically, transcriptomic alterations during opioid dependence were reflected more prominently in glial populations rather than in neurons specifically in the Oprm1 GG mice. By combining gene co-expression, pathway activity, and network remodeling across cell types and regions, we link Oprm1-driven genetic risk to anatomically organized shifts in glial, neuronal, and network function, defining the molecular basis of opioid dependence shaped by genetic background.