Neuropathic pain is usually persistent due to maladaptive neuroplasticity-induced central sensitization and, therefore, necessitates long-term treatment. N-methyl-D-aspartate receptor (NMDAR)-mediated hypersensitivity in the spinal dorsal horn represents key mechanisms of central sensitization. Short-term use of NMDAR antagonists produces antinociceptive efficacy in animal pain models and in clinical practice by reducing central sensitization. However, how prolonged use of NMDAR antagonists affects central sensitization remains unknown. Surprisingly, we find that prolonged blockage of NMDARs does not prevent but aggravate nerve injury-induced central sensitization and produce analgesic tolerance, mainly due to reduced synaptic inhibition. The disinhibition that results from the continuous decrease in the production of nitric oxide from neuronal nitric oxide synthase, downstream signal of NMDARs, leads to the reduction of GABAergic inhibitory synaptic transmission by upregulating brain-derived neurotrophic factor expression and inhibiting the expression and function of potassium-chloride cotransporter. Together, our findings suggest that chronic blockage of NMDARs develops analgesic tolerance through the neuronal nitric oxide synthase–brain-derived neurotrophic factor–potassium-chloride cotransporter pathway. Thus, preventing the GABAergic disinhibition induced by nitric oxide reduction may be necessary for the long-term maintenance of the analgesic effect of NMDAR antagonists.

由于适应不良的神经可塑性引起的中枢敏化，神经性疼痛通常是持续性的，因此需要长期治疗。 N-甲基-D-天冬氨酸受体（NMDAR）介导的脊髓背角超敏反应代表了中枢敏化的关键机制。短期使用 NMDAR 拮抗剂可通过减少中枢敏化在动物疼痛模型和临床实践中产生镇痛功效。然而，长期使用 NMDAR 拮抗剂如何影响中枢敏化仍不清楚。令人惊讶的是，我们发现长时间阻断 NMDAR 并不能预防而是会加剧神经损伤引起的中枢敏化并产生镇痛耐受，这主要是由于突触抑制减少。神经元一氧化氮合酶（NMDAR 的下游信号）产生一氧化氮的持续减少导致去抑制，通过上调脑源性神经营养因子表达并抑制钾的表达和功能，导致 GABA 能抑制性突触传递减少。 -氯离子协同转运蛋白。总之，我们的研究结果表明，长期阻断 NMDAR 可通过神经元一氧化氮合酶 - 脑源性神经营养因子 - 钾 - 氯化物协同转运蛋白途径产生镇痛耐受性。因此，防止一氧化氮还原引起的 GABA 能去抑制对于长期维持 NMDAR 拮抗剂的镇痛作用可能是必要的。