Intrathecal administration of the fat-mass and obesity-associated protein inhibitor mitigates neuropathic pain in female rats.
Intrathecal administration of the fat-mass and obesity-associated protein inhibitor mitigates neuropathic pain in female rats.
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DOI：
10.31480/2330-4871/163
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发表时间：
2022-12
期刊：
影响因子：
--
通讯作者：
Xiang Li;Yuan-Xiang Tao
中科院分区：
文献类型：
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作者：
Xiang Li;Yuan-Xiang Tao
几种细胞内信号参与慢性疼痛的性二型性。我们的前期研究表明，大鼠和小鼠背根神经节（DRG）损伤后，背根神经节内的脂肪量和肥胖相关蛋白（FTO）参与了神经损伤诱导的伤害性超敏反应的发生和维持。然而，DRG FTO的这些作用是否以性别依赖的方式仍然是未知的。本研究旨在探讨鞘内注射特异性FTO抑制剂甲氨酰胺酸（MA）对雌性大鼠慢性压迫性损伤（CCI）诱导的伤害性超敏反应的影响。在雌性大鼠中，鞘内注射MA在诱导期和维持期均减弱CCI诱导的机械性异常性疼痛、热痛觉过敏和冷痛觉过敏，而不改变急性/基础疼痛和运动功能。鞘内MA也阻断了CCI诱导的雌性大鼠同侧L4和L5背角神经元和星形胶质细胞的过度激活。从机制上讲，鞘内MA阻止了CCI诱导的组蛋白甲基转移酶G9 a表达增加，并逆转了雌性大鼠同侧L4和L5 DRG中μ阿片受体和Kv1.2蛋白的G9 a控制的下调。这些发现表明，FTO抑制剂对雌性大鼠神经损伤诱导的伤害性超敏反应的影响与先前报道的雄性大鼠相似。我们的数据还进一步证实了DRG FTO在神经性疼痛中的作用，并表明FTO抑制剂在男性和女性中预防和治疗这种疾病的潜在临床应用。
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 N6-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.