Caudle Robert M, Perez Federico M, Del Valle-Pinero Arseima Y, Iadarola Michael J
Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL 32610, USA.
Mol Pain. 2005 Sep 2;1:25. doi: 10.1186/1744-8069-1-25.
Spinal cord N-methyl-D-aspartate (NMDA) receptors are intimately involved in the development and maintenance of central sensitization. However, the mechanisms mediating the altered function of the NMDA receptors are not well understood. In this study the role of phosphorylation of NR1 splice variants and NR2 subunits was examined following hind paw inflammation in rats. We further examined the level of expression of these proteins following the injury.
Lumbar spinal cord NR1 subunits were found to be phosphorylated on serine residues within two hours of the induction of hind paw inflammation with carrageenan. The enhanced NR1 serine phosphorylation reversed within six hours. No phosphorylation on NR1 threonine or tyrosine residues was observed. Likewise, no NR2 subunit phosphorylation was observed on serine, threonine or tyrosine residues. An analysis of NR1 and NR2 protein expression demonstrated no change in the levels of NR1 splice variants or NR2A following the inflammation. However, spinal cord NR2B expression was depressed by the hind paw inflammation. The expression of NR2B remained depressed for more than one week following initiation of the inflammation.
These data suggest that NR1 serine phosphorylation leads to an initial increase in NMDA receptor activity in the spinal cord following peripheral injury. The suppression of NR2B expression suggests compensation for the enhanced nociceptive activity. These data indicate that spinal cord NMDA receptors are highly dynamic in the development, maintenance and recovery from central sensitization following an injury. Thus, chronic pain therapies targeted to NMDA receptors should be designed for the exact configuration of NMDA receptor subunits and post-translational modifications present during specific stages of the disease.
脊髓N-甲基-D-天冬氨酸（NMDA）受体与中枢敏化的发生和维持密切相关。然而，介导NMDA受体功能改变的机制尚未完全明确。在本研究中，我们检测了大鼠后爪炎症后NR1剪接变体和NR2亚基磷酸化的作用。我们还进一步检测了损伤后这些蛋白的表达水平。
用角叉菜胶诱导大鼠后爪炎症后两小时内，发现腰段脊髓NR1亚基的丝氨酸残基发生磷酸化。增强的NR1丝氨酸磷酸化在6小时内逆转。未观察到NR1苏氨酸或酪氨酸残基的磷酸化。同样，未观察到NR2亚基丝氨酸、苏氨酸或酪氨酸残基的磷酸化。对NR1和NR2蛋白表达的分析表明，炎症后NR1剪接变体或NR2A的水平没有变化。然而，后爪炎症使脊髓NR2B的表达降低。炎症开始后，NR2B的表达持续降低超过一周。
这些数据表明，外周损伤后，NR1丝氨酸磷酸化导致脊髓中NMDA受体活性最初增加。NR2B表达的抑制表明对增强的伤害性感受活性的一种代偿。这些数据表明，脊髓NMDA受体在损伤后中枢敏化的发生、维持和恢复过程中具有高度的动态变化。因此，针对NMDA受体的慢性疼痛治疗应根据疾病特定阶段存在的NMDA受体亚基的确切构型和翻译后修饰来设计。
