Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.
Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China
Reg Anesth Pain Med. 2021 Apr;46(4):363-373. doi: 10.1136/rapm-2020-101883. Epub 2020 Dec 18.
Prolonged postoperative pain is a major concern and occurs more frequently in women, but mechanisms remain elusive. NR2B-containging N-methyl-d-aspartate (NMDA) receptor is a key component of nociception transduction. Divalent metal transporter 1 (DMT1)-mediated iron overload involves NMDA-induced neurotoxicity in males. Kalirin-7 is vital in synaptic plasticity underlying pathological pain in males. Herein, the requirement for kalirin-7 in NR2B phosphorylation-dependent iron accumulation and spine plasticity in postoperative pain after tibial fracture in female mice has been examined.
Pain-related behavior, spinal NR2B phosphorylation at Tyr1472, kalirin-7 expression, DMT1 with/without iron-responsive element (IRE (+) DMT1 and IRE (-) DMT1) level, iron concentration and spine morphology were assessed in females. NR2B antagonist Ro25-6981, iron chelator deferoxamine and kalirin-7 knockdown by short hairpin RNA were employed to assess the potential cascade.
Tibial fracture initiates long-term allodynia lasting at least 21 days postoperatively, and upregulates spinal NR2B phosphorylation, kalirin-7 and IRE (-) DMT1 expression, iron overload and spine density. Ro25-6981 reduces postoperative mechanical and cold allodynia, spinal NR2B phosphorylation, kalirin-7 level and IRE (-) DMT1-mediated iron overload. Kalirin-7 knockdown impairs fracture-associated allodynia, IRE (-) DMT1-mediated iron overload and spine plasticity. Deferoxamine also attenuates behavioral allodynia and spine plasticity. Spinal NMDA application elicits NR2B-dependent mechanical allodynia and iron overload, which is reversed by kalirin-7 knockdown or coadministration of deferoxamine.
Spinal NR2B phosphorylation at Tyr1472 upregulates kalirin-7 expression to facilitate IRE (-) DMT1-mediated iron accumulation and spine morphogenesis in the development of fracture-associated postoperative pain in female mice.
术后长期疼痛是一个主要关注点，女性中更为常见，但机制仍不清楚。NR2B 含有 N-甲基-D-天冬氨酸（NMDA）受体是伤害感受转导的关键组成部分。二价金属转运蛋白 1（DMT1）介导的铁过载涉及 NMDA 诱导的雄性神经毒性。Kalirin-7 在雄性病理性疼痛的突触可塑性中至关重要。在此，研究了在雌性小鼠胫骨骨折后术后疼痛中，kalirin-7 在 NR2B 磷酸化依赖性铁积累和脊柱重塑中的作用。
评估了疼痛相关行为、脊髓 NR2B 在 Tyr1472 处的磷酸化、kalirin-7 表达、DMT1（有/无铁反应元件（IRE(+)DMT1 和 IRE(-)DMT1）水平、铁浓度和脊柱形态。使用 NR2B 拮抗剂 Ro25-6981、铁螯合剂去铁胺和短发夹 RNA 敲低 kalirin-7 来评估潜在的级联反应。
胫骨骨折引发至少持续 21 天的长期痛觉过敏，上调脊髓 NR2B 磷酸化、kalirin-7 和 IRE(-)DMT1 表达、铁过载和脊柱密度。Ro25-6981 可减轻术后机械性和冷性痛觉过敏、脊髓 NR2B 磷酸化、kalirin-7 水平和 IRE(-)DMT1 介导的铁过载。kalirin-7 敲低可损害骨折相关痛觉过敏、IRE(-)DMT1 介导的铁过载和脊柱可塑性。去铁胺也可减轻行为性痛觉过敏和脊柱重塑。脊髓 NMDA 应用引发 NR2B 依赖性机械性痛觉过敏和铁过载，这可通过 kalirin-7 敲低或去铁胺共同给药逆转。
脊髓 NR2B 在 Tyr1472 处的磷酸化可上调 kalirin-7 表达，以促进 IRE(-)DMT1 介导的铁积累和脊柱形态发生，从而导致雌性小鼠骨折相关术后疼痛的发展。
