The Role of NMDA and NK1 Receptor Signaling in Spine Surgery-induced Central Sensitization

Study Design. Double-blinded, prospective laboratory animal study. Objective. To examine the mechanism of spine surgery-induced central sensitization. Summary of Background Data. 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. Materials and Methods. 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. Results. 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). Conclusions. 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.