Dopamine receptor D2 regulates GLUA1-containing AMPA receptor trafficking and central sensitization through the PI3K signaling pathway in a male rat model of chronic migraine

作者全名："Zhang, Wei; Lei, Ming; Wen, Qianwen; Zhang, Dunke; Qin, Guangcheng; Zhou, Jiying; Chen, Lixue"

作者地址："[Zhang, Wei; Lei, Ming; Wen, Qianwen; Zhang, Dunke; Qin, Guangcheng; Chen, Lixue] Chongqing Med Univ, Lab Res Ctr, Affiliated Hosp 1, 1st You Yi Rd, Chongqing 400016, Peoples R China; [Zhou, Jiying] Chongqing Med Univ, Dept Neurol, Affiliated Hosp 1, Chongqing, Peoples R China"

通信作者："Chen, LX (通讯作者)，Chongqing Med Univ, Lab Res Ctr, Affiliated Hosp 1, 1st You Yi Rd, Chongqing 400016, Peoples R China."

来源：JOURNAL OF HEADACHE AND PAIN

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000838634300002

JCR分区：Q1

影响因子：7.4

年份：2022

卷号：23

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Chronic migraine; Dopamine D2 receptor; GLUA1-containing AMPA receptor trafficking; Central sensitization

摘要："Background The pathogenesis of chronic migraine remains unresolved. Recent studies have affirmed the contribution of GLUA1-containing AMPA receptors to chronic migraine. The dopamine D2 receptor, a member of G protein-coupled receptor superfamily, has been proven to have an analgesic effect on pathological headaches. The present work investigated the exact role of the dopamine D2 receptor in chronic migraine and its effect on GLUA1-containing AMPA receptor trafficking. Methods A chronic migraine model was established by repeated inflammatory soup stimulation. Mechanical, periorbital, and thermal pain thresholds were assessed by the application of von Frey filaments and radiant heat. The mRNA and protein expression levels of the dopamine D2 receptor were analyzed by qRT-PCR and western blotting. Colocalization of the dopamine D2 receptor and the GLUA1-containing AMPAR was observed by immunofluorescence. A dopamine D2 receptor agonist (quinpirole) and antagonist (sulpiride), a PI3K inhibitor (LY294002), a PI3K pathway agonist (740YP), and a GLUA1-containing AMPAR antagonist (NASPM) were administered to confirm the effects of the dopamine D2 receptor, the PI3K pathway and GULA1 on central sensitization and the GLUA1-containing AMPAR trafficking. Transmission electron microscopy and Golgi-Cox staining were applied to assess the impact of the dopamine D2 receptor and PI3K pathway on synaptic morphology. Fluo-4-AM was used to clarify the role of the dopamine D2 receptor and PI3K signaling on neuronal calcium influx. The Src family kinase (SFK) inhibitor PP2 was used to explore the effect of Src kinase on GLUA1-containing AMPAR trafficking and the PI3K signaling pathway. Results Inflammatory soup stimulation significantly reduced pain thresholds in rats, accompanied by an increase in PI3K-P110 beta subunit expression, loss of dopamine receptor D2 expression, and enhanced GLUA1-containing AMPA receptor trafficking in the trigeminal nucleus caudalis (TNC). The dopamine D2 receptor colocalized with the GLUA1-containing AMPA receptor in the TNC; quinpirole, LY294002, and NASPM alleviated pain hypersensitivity and reduced GLUA1-containing AMPA receptor trafficking in chronic migraine rats. Sulpiride aggravated pain hypersensitivity and enhanced GLUA1 trafficking in CM rats. Importantly, the anti-injury and central sensitization-mitigating effects of quinpirole were reversed by 740YP. Both quinpirole and LY294002 inhibited calcium influx to neurons and modulated the synaptic morphology in the TNC. Additional results suggested that DRD2 may regulate PI3K signaling through Src family kinases. Conclusion Modulation of GLUA1-containing AMPA receptor trafficking and central sensitization by the dopamine D2 receptor via the PI3K signaling pathway may contribute to the pathogenesis of chronic migraine in rats, and the dopamine D2 receptor could be a valuable candidate for chronic migraine treatment."

基金机构：National Natural Science Foundation of China [:81671093]

基金资助正文：This work was supported by the National Natural Science Foundation of China (No:81671093).