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Spinal NR2B phosphorylation at Tyr1472 regulates IRE(−)DMT1-mediated iron accumulation and spine morphogenesis via kalirin-7 in tibial fracture-associated postoperative pain after orthopedic surgery in female mice


Background 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.

Methods 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.

Results 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.

Conclusion 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.

  • injections
  • spinal
  • pain
  • postoperative
  • pain management
  • chronic pain

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