Runx1 transcription factor modulates opioid analgesia and withdrawal in humans and rodents.
Opioid analgesia and adverse outcomes vary across individuals. We show that runt-related transcription factor 1 (Runx1) modulates the microglial transcriptome and is a genetic determinant of opioid antinociceptive responses and withdrawal. In mice, Runx1 deletion in microglia produces distinct ultrastructural and transcriptomic signatures, reducing morphine potency despite no prior opioid exposure. These mice also require greater post-operative morphine and display exacerbated morphine-induced hyperalgesia and withdrawal. Single-cell RNA sequencing (scRNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses reveal a unique microglial state, with Runx1 regulating inflammatory signaling and key microglial functions. In humans, association analyses link RUNX1 variants to inter-individual differences in perioperative opioid requirement and withdrawal severity. Identifying RUNX1 susceptibility genotypes may be important for understanding individual variability in opioid responses, with potential relevance for future personalized approaches.
Authors
Leduc-Pessah Leduc-Pessah, McAllister McAllister, Sinha Sinha, Stokes-Heck Stokes-Heck, Nishizawa Nishizawa, Fan Fan, St-Pierre St-Pierre, Bradaia Bradaia, Defaye Defaye, Burma Burma, Damblon Damblon, Muñoz-Pino Muñoz-Pino, Visser Visser, Dorion Dorion, Healy Healy, Tang Tang, Canet-Pons Canet-Pons, van den Hoogen van den Hoogen, Zhang Zhang, Antunes Antunes, Piscopo Piscopo, Medina Medina, Fukuda Fukuda, Ichinohe Ichinohe, Nagashima Nagashima, Hayashida Hayashida, Johnson Johnson, Agrawal Agrawal, Degenhardt Degenhardt, Martin Martin, Zamponi Zamponi, Nelson Nelson, Altier Altier, Tremblay Tremblay, Bousman Bousman, Stifani Stifani, De Koninck De Koninck, Ikeda Ikeda, Biernaskie Biernaskie, Trang Trang
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