Department of Pharmacology, School of Pharmacy, 12644Fourth Military Medical University, Xi'an, China.
State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Pharmacy, School of Stomatology, 12644Fourth Military Medical University, Xi'an, China.
Mol Pain. 2020 Jan-Dec;16:1744806920972241. doi: 10.1177/1744806920972241.
Visceral pain is a common clinical symptom, which is caused by mechanical stretch, spasm, ischemia and inflammation. Fragile X syndrome (FXS) with lack of fragile X mental retardation protein (FMRP) protein is an inherited disorder that is characterized by moderate or severe intellectual and developmental disabilities. Previous studies reported that FXS patients have self-injurious behavior, which may be associated with deficits in nociceptive sensitization. However, the role of FMRP in visceral pain is still unclear. In this study, the knock out (KO) mice and SH-SY5Y cell line were employed to demonstrate the role of FMRP in the regulation of visceral pain. The data showed that KO mice were insensitive to zymosan treatment. Recording in the anterior cingulate cortex (ACC), a structure involved in pain process, showed less presynaptic glutamate release and postsynaptic responses in the KO mice as compared to the wild type (WT) mice after zymosan injection. Zymosan treatment caused enhancements of adenylyl cyclase 1 (AC1), a pain-related enzyme, and NMDA GluN2B receptor in the ACC. However, these up-regulations were attenuated in the ACC of KO mice. Last, we found that zymosan treatment led to increase of FMRP levels in the ACC. These results were further confirmed in SH-SY5Y cells in vitro. Our findings demonstrate that FMRP is required for NMDA GluN2B and AC1 upregulation, and GluN2B/AC1/FMRP forms a positive feedback loop to modulate visceral pain.
内脏痛是一种常见的临床症状，由机械拉伸、痉挛、缺血和炎症引起。脆性 X 综合征（FXS）是一种遗传性疾病，其特征是中度或重度智力和发育障碍，缺乏脆性 X 智力低下蛋白（FMRP）。先前的研究报道 FXS 患者有自伤行为，这可能与伤害感受敏化缺陷有关。然而，FMRP 在内脏痛中的作用尚不清楚。在这项研究中，敲除（KO）小鼠和 SH-SY5Y 细胞系被用来证明 FMRP 在调节内脏痛中的作用。数据显示，KO 小鼠对酵母聚糖处理不敏感。在涉及疼痛过程的前扣带皮层（ACC）中记录到，与野生型（WT）小鼠相比，KO 小鼠在酵母聚糖注射后，突触前谷氨酸释放和突触后反应较少。酵母聚糖处理导致与疼痛相关的酶腺苷酸环化酶 1（AC1）和 NMDA GluN2B 受体在 ACC 中的表达增强。然而，这些上调在 KO 小鼠的 ACC 中被减弱。最后，我们发现酵母聚糖处理导致 ACC 中 FMRP 水平增加。这些结果在体外的 SH-SY5Y 细胞中得到了进一步证实。我们的研究结果表明，FMRP 是 NMDA GluN2B 和 AC1 上调所必需的，并且 GluN2B/AC1/FMRP 形成正反馈回路来调节内脏痛。
