Yamamoto Satoshi, Fang Jaden, Eter Asia, Liu Grace, Nguyen Amber, Chung Jin-Mo, La Jun-Ho
Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX.
Department of Neurobiology, University of Texas Medical Branch, Galveston, TX.
Spine (Phila Pa 1976). 2025 Aug 15;50(16):1120-1126. doi: 10.1097/BRS.0000000000005382. Epub 2025 May 1.
Double-blinded, prospective laboratory animal study.
To examine the mechanism of spine surgery-induced central sensitization.
We previously established a mouse model of spine surgery-induced central sensitization manifested as mechanical hypersensitivity outside the surgery area. As mitigating this central sensitization development is expected to reduce postoperative pain after spine surgery, here we investigated its mechanisms using the model, focusing on the role of spinal N-methyl-D-aspartate (NMDA) and Neurokinin 1 (NK1) receptors.
Hind paw withdrawal thresholds were longitudinally measured using the von Frey assay. The expression of NMDA and NK1 receptors in the dorsal horn (DH) was quantified using western blot. Data were analyzed using ANOVA/mixed-effects analysis followed by Sidak/Dunnett multiple comparison tests.
Presurgical antagonism of NMDA or NK1 receptors at the spinal level dose-dependently inhibited the development of laminectomy-induced central sensitization ( P <0.0001 for the antagonist effect by ANOVA/mixed effect analysis in each antagonist, sex, and hind paw). Compared with sham surgery, laminectomy upregulated the expression of NMDA subunits GluN1 [t(22)=3.43, P =0.0045 in ipsilateral DH; t(21)=2.54, P =0.035 in contralateral DH] and GluN2B [t(17)=2.49, P =0.042 in ipsilateral DH; t(17)=3.72, P =0.0032 in contralateral DH], and the NK1 receptor [t(21)=2.48, P =0.039 in ipsilateral DH; t(21)=2.76, P =0.022 in contralateral DH] in females. In males, laminectomy upregulated GluN1 only in the ipsilateral DH [t(12)=2.62, P =0.04], GluN2B only in the contralateral DH [t(12)=2.69, P =0.036], and the NK1 receptor in both sides [t(21)=3.60, P =0.0032 in ipsilateral DH; t(23)=2.60, P =0.029 in contralateral DH]. This upregulation was mitigated by presurgical antagonism of spinal NMDA or NK1 receptors ( P >0.12 vs. sham in all groups).
The findings highlight the role of NMDA and NK1 receptor stimulation/upregulation in central sensitization caused by spine surgery. Targeting these receptors presurgically presents a promising strategy to prevent hypersensitivity development and improve postoperative pain management for spine surgery patients.
双盲前瞻性实验动物研究。
研究脊柱手术诱导中枢敏化的机制。
我们之前建立了一个脊柱手术诱导中枢敏化的小鼠模型，表现为手术区域外的机械性超敏反应。由于减轻这种中枢敏化的发展有望减轻脊柱手术后的疼痛，因此我们在此使用该模型研究其机制，重点关注脊髓N-甲基-D-天冬氨酸（NMDA）和神经激肽1（NK1）受体的作用。
使用von Frey试验纵向测量后爪缩足阈值。采用蛋白质免疫印迹法对脊髓背角（DH）中NMDA和NK1受体的表达进行定量分析。数据采用方差分析/混合效应分析，随后进行Sidak/Dunnett多重比较检验。
术前在脊髓水平拮抗NMDA或NK1受体可剂量依赖性抑制椎板切除术诱导的中枢敏化的发展（在每种拮抗剂、性别和后爪中，通过方差分析/混合效应分析，拮抗剂效应P<0.0001）。与假手术相比，椎板切除术使雌性小鼠同侧DH中NMDA亚基GluN1[t(22)=3.43，P =0.0045]、对侧DH中GluN1[t(21)=2.54，P =0.035]、同侧DH中GluN2B[t(17)=2.49，P =0.042]、对侧DH中GluN2B[t(17)=3.72，P =0.0032]以及NK1受体[t(21)=2.48，P =0.039]的表达上调；使雄性小鼠同侧DH中仅GluN1[t(12)=2.62，P =0.04]、对侧DH中仅GluN2B[t(12)=2.69，P =0.036]以及双侧NK1受体[t(21)=3.60，P =0.0032（同侧DH）；t(23)=2.60，P =0.029（对侧DH）]的表达上调。术前拮抗脊髓NMDA或NK1受体可减轻这种上调（与假手术组相比，所有组P>0.12）。
这些发现突出了NMDA和NK1受体刺激/上调在脊柱手术引起的中枢敏化中的作用。术前针对这些受体是预防超敏反应发展和改善脊柱手术患者术后疼痛管理的一种有前景的策略。
