Wang Jian, Xu Wei, Shao Jiali, He Zhenghua, Ding Zhuofeng, Huang Jiangju, Guo Qulian, Zou Wangyuan
Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Oncotarget. 2017 Apr 25;8(17):28203-28214. doi: 10.18632/oncotarget.15997.
Morphine tolerance is a clinical challenge in pain management. Emerging evidence suggests that microRNA (miRNA) plays a regulatory role in the development of morphine tolerance. miR-219-5p (miR-219) targets calmodulin-dependent protein kinase II γ (CaMKIIγ) to activate central pain sensitization via N-methyl-D-aspartate (NMDA) receptor. Therefore, we hypothesized that miR-219-5p attenuates morphine tolerance by targeting CaMKIIγ. We found that the expression of miR-219-5p was decreased significantly after chronic morphine treatment. Overexpression of miR-219-5p by lentivirus injection prevents the development of morphine tolerance. CaMKIIγ, the target gene of miR-219-5p was downregulated by overexpression of miR-219-5p both in vivo and in vitro. Furthermore, we found that lentiviral-mediated miR-219-5p decreased the expression of NMDA receptor subunit 1 (NR1), leading to attenuation of morphine tolerance. Overall, the data demonstrate that miR-219-5p plays a crucial role in alleviating morphine tolerance by inhibiting the CaMKII/NMDA receptor pathway. Overexpression of miR-219-5p may be a potential strategy to ameliorate morphine tolerance.
吗啡耐受性是疼痛管理中的一项临床挑战。新出现的证据表明，微小RNA（miRNA）在吗啡耐受性的发展中起调节作用。miR-219-5p（miR-219）靶向钙调蛋白依赖性蛋白激酶IIγ（CaMKIIγ），通过N-甲基-D-天冬氨酸（NMDA）受体激活中枢性疼痛敏化。因此，我们推测miR-219-5p通过靶向CaMKIIγ减轻吗啡耐受性。我们发现，慢性吗啡治疗后miR-219-5p的表达显著降低。通过慢病毒注射过表达miR-219-5p可预防吗啡耐受性的发展。miR-219-5p的靶基因CaMKIIγ在体内和体外均因miR-219-5p的过表达而下调。此外，我们发现慢病毒介导的miR-219-5p降低了NMDA受体亚基1（NR1）的表达，导致吗啡耐受性减弱。总体而言，数据表明miR-219-5p通过抑制CaMKII/NMDA受体途径在减轻吗啡耐受性中起关键作用。过表达miR-219-5p可能是改善吗啡耐受性的一种潜在策略。
