Reversible m 6 Am methylation of snRNA by FTO controls morphine reward and tolerance without altering analgesia
Year: 2026
Type: preprint
Abstract: Mu opioids, such as morphine, are effective analgesics, but they produce reward and tolerance that lead to opioid use disorder. A major goal is to achieve analgesia without these harmful effects. Here we show that morphine reward and tolerance are controlled by a reversible RNA modification in small nuclear RNA (snRNA) that is removed by the RNA demethylase FTO. Genetic depletion and pharmacologic inhibition of FTO each reduced morphine reward, measured by conditioned-place preference, and reduced tolerance to morphine and fentanyl, without altering analgesia. Depleting Fto in the nucleus accumbens shell reduced reward but not tolerance, while depleting Fto in the dorsal root ganglion reduced tolerance but not reward, suggesting region-specific effects of FTO. Although FTO is known to erase m 6 A on mRNA, we found no effect of FTO depletion on m 6 A sites, but a marked increase in m 6 Am levels in snRNA. The effects of FTO depletion were suppressed in mice that cannot make m 6 Am, supporting the importance of elevated m 6 Am in suppressing morphine reward and tolerance. Consistent with altered snRNA function, FTO depletion reshapes gene expression linked to morphine signaling. FTO inhibitors may therefore provide useful adjuvants for mu opioids in pain management and treatment of opioid use disorder.
Source: Research Square
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7202257612