Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, United States.
Department of Anesthesia, University of Iowa, Iowa City, IA, United States.
Brain Res. 2021 Jan 1;1750:147154. doi: 10.1016/j.brainres.2020.147154. Epub 2020 Oct 14.
Activation of Ca/calmodulin kinase II (CaMKII) and the N-Methyl D-aspartate receptor (NMDAR), particularly its GluN2B subunit, contribute to the central sensitization of nociceptive pathways and persistent pain. Using mutant mice wherein the activity-driven binding of CaMKII to S1303 in GluN2B is abrogated (GluN2BKI), this study investigated the importance of this interaction for acute and persistent inflammatory nociception. GluN2BKI, wild type and heterozygote mice did not differ in responses to acute noxious heat stimuli as measured with tail flick, paw flick, or hot plate assays, nor did they differ in their responses to mechanical stimulation with von Frey filaments. Surprisingly, the three genotypes exhibited similar spontaneous pain behaviors and hypersensitivity to heat or mechanical stimuli induced by intraplantar injection of capsaicin; however, GluN2BKI mice did not immediately attend to the paw. WT and GluN2BKI mice also did not differ in the nociceptive behaviors elicited by intraplantar injection of formalin, even though MK801 greatly reduced these behaviors in both genotypes concordant with NMDAR dependence. CaMKII binding to GluN2B at S1303 therefore does not appear to be critical for the development of inflammatory nociception. Finally, intrathecal KN93 reduced formalin-induced nociceptive behaviors in GluN2BKI mice. KN93 does not inhibit CaKMII, but rather binds Ca/calmodulin. It has multiple other targets including Ca-, Na- and K-channels, as well as various kinases. Therefore, the use of GluN2BKI mice provided genetic specificity in assessing the role of CaMKII in inflammatory pain signaling cascades. These results challenge current thinking on the involvement of the CaMKII-NMDAR interaction in inflammatory pain.
钙/钙调蛋白激酶 II（CaMKII）和 N-甲基-D-天冬氨酸受体（NMDAR）的激活，特别是其 GluN2B 亚基，有助于伤害性通路的中枢敏化和持续性疼痛。本研究使用活性驱动 CaMKII 与 GluN2B 的 S1303 结合被阻断的突变小鼠（GluN2BKI），研究了这种相互作用对急性和持续性炎症性疼痛的重要性。GluN2BKI、野生型和杂合子小鼠在尾 flick、爪 flick 或热板试验中对急性有害热刺激的反应没有差异，也没有在对 von Frey 纤维机械刺激的反应中存在差异。令人惊讶的是，这三种基因型表现出相似的自发性疼痛行为和对足底注射辣椒素诱导的热或机械刺激的超敏反应；然而，GluN2BKI 小鼠不会立即关注爪子。WT 和 GluN2BKI 小鼠在足底注射福尔马林引起的痛觉行为中也没有差异，尽管 MK801 大大减少了这两种基因型的这些行为，这与 NMDAR 依赖性一致。因此，CaMKII 与 GluN2B 的 S1303 结合似乎对于炎症性疼痛的发展并不关键。最后，鞘内 KN93 减少了 GluN2BKI 小鼠中福尔马林引起的痛觉行为。KN93 不抑制 CaKMII，而是结合 Ca/钙调蛋白。它还有多个其他靶点，包括 Ca、Na 和 K 通道，以及各种激酶。因此，使用 GluN2BKI 小鼠在评估 CaMKII 在炎症性疼痛信号级联中的作用时提供了遗传特异性。这些结果挑战了当前关于 CaMKII-NMDAR 相互作用在炎症性疼痛中的参与的思维。
