A non-toxic analgesic elicits cell-specific genomic and epigenomic modulation by targeting the PAG brain region

Acetaminophen (ApAP) is widely used for pain management, but overuse or overdose leads to hepatotoxicity, making it the leading cause of acute liver failure globally. There is an urgent need for safer pain medications, as other non-opioid analgesics like non-steroidal anti-inflammatory drugs (NSAIDs) are nephrotoxic. We have identified SRP-001 as a safer, non-hepatotoxic, novel analgesic that overcomes ApAP’s limitations by avoiding NAPQI formation and preserving hepatic tight junctions. Using coupled RNA and ATAC sequencing, we compared the genetic and epigenetic signatures of SRP-001 and ApAP treatments following complete Freund’s adjuvant (CFA)-induced inflammatory pain against no treatment and vehicle controls. Multiome sequencing (snRNA and snATAC) of PAG following CFA induced pain treated with analgesic drugs ApAP or SRP-001 compared to control and CFA induced pain with no treatment to determine genetic and epigenetic changes with analgesic treatment