Many of the genes and pathways enriched in specific striatal cell types of individuals with OUD have been implicated in various processes related to cell stress and senescence, DNA damage, and inflammation. Opioids lead to persistent changes in neuronal activity and synaptic plasticity within the striatum. Prolonged or repeated alterations in neuronal activity combined with dysfunction within DNA repair pathways hampered by persistent cell stress (e.g., oxidative stress) may lead to the accumulation of DNA damage. Neurons may be particularly vulnerable to DNA damage105, in that breaks in the DNA and subsequent DNA repair, allow neurons to respond rapidly at the transcriptional level to changes in activity106,107. DNA integrity is critical for neural cells to prevent insertions, deletions, or mutations that ultimately have consequences on cell health and function. Our results suggest elevated DNA damage in neurons of individuals with OUD, particularly within striatal interneurons.
