factors, such as stress, neuroinflammation, and hypoxia (Fig. 3), associated with OUD and opioid overdose. Interestingly, hypoxia pathways were significantly downregulated in OUD (Fig. 3d; Supplementary Data 1-S9), including decreased expression of genes that are activated in response to hypoxic events (e.g., NMRK1, BHLHE40; Fig. 3a)81, and overexpression of hypoxia-inducible transcription factor, HIF1A. Therefore, while respiratory depression is a hallmark of opioid overdose, downregulation of hypoxia-responsive genes points toward possible compensation in neurons secondary to periodic hypoxia and altered redox states, consistent with rodent models of substance use82.
