Deciphering the molecular transcriptome underlying nociceptive sensitization through human intraoperative tissue sampling

Authors

• E Li
• MR Sapio
• AF Domenichiello
• T Goto
• D Maric
• A Manalo
• TS Williams
• DS Schrump
• JL Davis
• JM Hernandez
• AM Blakeley
• MJ Iadarola
• AJ Mannes

Abstract

Developing non-opioid analgesics for improved postoperative pain management is a major goal of the pain field. The present study investigates gene transduction underlying early nociceptive signaling following tissue injury in clinical surgical cases using transcriptomics and multiplex fluorescence in situ hybridization to understand the most significant genes induced by surgery and localize induction events to anatomic structures. Tissue samples were longitudinally collected from patients (n=12; 7 Female and 5 Male) at surgery onset (0 hours), prespecified timepoints during surgery (1, 2, 4, 6 hours), and surgical closure (≥8 hours). At the whole-transcriptome level, most genes continually increased or decreased after incision. We specifically investigated induction of consequential secreted signaling molecules involved in immune cell recruitment, inflammation, and nociception pathways, including interleukins 6 and 8, oncostatin M, and chemokine ligands 1 and 2. Subsequently, we localized transcripts superficially in the epidermis and deeper in blood vasculature, hair follicles, and sweat glands. We further assessed the potential for long-range signaling of secreted molecules from damaged skin to the dorsal root ganglion (DRG) by examining human DRG receptor expression of these factors. We observed DRG neuronal expression of receptors for various key genes including interleukin 6, prostaglandin E2, oncostatin M, and leukemia inhibitory factor, suggesting their role in conducting peripheral sensitization leading to persistent pain. Our findings reveal a nexus of signaling molecules involved in the early pain response that ultimately drives pathways of nerve terminal sensitization and algesia mediation. This abstract is based on a clinical trial registered at ClinicalTrials.gov (NCT04224870).

Scientific Focus Area: Neuroscience

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