Intrathecal administration of the fat-mass and obesity-associated protein inhibitor mitigates neuropathic pain in female rats.

Several intracellular signals are involved in the sexual dimorphism of chronic pain. Our previous studies demonstrated that the fat-mass and obesity-associated protein (FTO), a demethylase of RNA 6-methyladenosine, in the injured dorsal root ganglion (DRG) contributed to the development and maintenance of nerve injury-induced nociceptive hypersensitivity in male rats and male mice. However, whether these effects of DRG FTO are in a sex-dependent manner is still unknown. The present study sought to investigate the effect of intrathecal administration of a specific FTO inhibitor, meclofenamic acid (MA), on chronic constriction injury (CCI)-induced nociceptive hypersensitivity in female rats. Intrathecal injection of MA attenuated the CCI-induced mechanical allodynia, heat hyperalgesia, and cold hyperalgesia in both the induction and maintenance periods, without changing acute/basal pain and locomotor function, in female rats. Intrathecal MA also blocked the CCI-induced hyperactivations of neurons and astrocytes in the ipsilateral L4 and L5 dorsal horns of female rats. Mechanistically, intrathecal MA prevented the CCI-induced increase in the histone methyltransferase G9a expression and reversed the G9a-controlled downregulation of mu-opioid receptor and Kv1.2 proteins in the ipsilateral L4 and L5 DRGs of female rats. These findings indicate that the effects of the FTO inhibitor on nerve injury-induced nociceptive hypersensitivity in female rats are similar to those in male rats reported previously. Our data also further confirm the role of DRG FTO in neuropathic pain and suggest potential clinical application of the FTO inhibitors for the prevention and treatment of this disorder in both men and women.