Reversible m ⁶ Am methylation of snRNA by FTO controls morphine reward and tolerance without altering analgesia

<jats:p> Mu opioids, such as morphine, are effective analgesics, but their reward and tolerance drive opioid use disorder. A major goal is to achieve analgesia without these harmful effects. Here we show that morphine reward and tolerance require the RNA demethylase FTO. Genetic depletion and pharmacologic inhibition of FTO each reduced morphine reward, measured by conditioned-place preference, and reduced antinociceptive tolerance to morphine and fentanyl, without altering analgesia. Although FTO is known to erase m <jats:sup>6</jats:sup> A on mRNA, we found no effect of FTO depletion on m6A sites, but markedly increased levels of m <jats:sup>6</jats:sup> Am on snRNA. The effects of FTO depletion were suppressed in mice that cannot make m <jats:sup>6</jats:sup> Am, supporting the role of m <jats:sup>6</jats:sup> Am in morphine reward and tolerance. We show that FTO depletion regulates a gene expression network linked to morphine signaling. FTO inhibitors may therefore provide useful adjuvants to mu opioids in pain management and treatment of opioid use disorder. </jats:p>