Using single nuclei transcriptomics technologies, we identified both canonical neuronal and glial cell types in human striatum (e.g., D1-MSNs and D2-MSNs), along with several of the less abundant cell types, including subclasses of striatal interneurons and D1/D2-hybrid neurons. We also characterized the expression of specific opioid receptor and endogenous ligand subclasses across cell types, highlighting expression patterns unique to human striatum. Our single nuclei findings provide further insights into the specific cell types that may be impacted in OUD, while highlighting several putative mechanisms in human striatal neuronal and glial subtypes. A common theme that emerged from our analyses was the involvement of processes related to neuroinflammation and cell stress in OUD, including a broad interferon response among glial cells and elevated DNA damage in neurons. DNA damage markers were identified in both the striatum of humans and monkeys, suggesting chronic opioid use associated with OUD leads to augmented DNA modifications (e.g., single- and double-stranded breaks, impaired DNA repair, and chromatin accessibility). Proinflammatory signaling, the involvement of microglia-dependent signaling in striatum, and alterations in synaptic signaling in OUD are consistent with previous bulk transcriptomics findings from postmortem brains of individuals with OUD2,5,9.
