Xu Qian, Zheng Qin, Cui Xiang, Cleland Andrew, Hincapie Juan, Raja Srinivasa N, Dong Xinzhong, Guan Yun
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD, United States.
Howard Hughes Medical Institute, Johns Hopkins University, School of Medicine, Baltimore, MD, United States.
Pain. 2025 Feb 1;166(2):428-437. doi: 10.1097/j.pain.0000000000003361. Epub 2024 Aug 13.
Spinal cord stimulation (SCS) is an effective modality for pain treatment, yet its underlying mechanisms remain elusive. Neurokinin 1 receptor-positive (NK1R + ) neurons in spinal lamina I play a pivotal role in pain transmission. To enhance our mechanistic understanding of SCS-induced analgesia, we investigated how different SCS paradigms modulate the activation of NK1R + neurons, by developing NK1R-Cre;GCaMP6s transgenic mice and using in vivo calcium imaging of superficial NK1R + neurons under anesthesia (1.5% isoflurane). Neurokinin 1 receptor-positive neurons in the lumbar spinal cord (L4-5) showed a greater activation by electrical test stimulation (TS, 3.0 mA, 1 Hz) at the hindpaw at 2 weeks after tibia-sparing nerve injury (SNI-t) than in naïve mice. Spinal cord stimulation was then delivered through a bipolar plate electrode placed epidurally at L1-2 level. The short-term 50-Hz high-intensity SCS (80% motor threshold [MoT], 10 minutes) induced robust and prolonged inhibition of NK1R + neuronal responses to TS in both naïve and SNI-t mice. The 30-minute 50-Hz and 900-Hz SCS applied at moderate intensity (50% MoT) also significantly inhibited neuronal responses in SNI-t mice. However, at low intensity (20% MoT), the 30-minute 900-Hz SCS only induced persistent neuronal inhibition in naïve mice, but not in SNI-t mice. In conclusion, both 10-minute high-intensity SCS and 30-minute SCS at moderate intensity inhibit the activation of superficial NK1R + neurons, potentially attenuating spinal nociceptive transmission. Furthermore, in vivo calcium imaging of NK1R + neurons provides a new approach for exploring the spinal neuronal mechanisms of pain inhibition by neuromodulation pain therapies.
脊髓刺激（SCS）是一种有效的疼痛治疗方式，但其潜在机制仍不清楚。脊髓I层中的神经激肽1受体阳性（NK1R +）神经元在疼痛传递中起关键作用。为了增强我们对SCS诱导镇痛机制的理解，我们通过开发NK1R-Cre;GCaMP6s转基因小鼠，并在麻醉（1.5%异氟醚）下对浅表NK1R +神经元进行体内钙成像，研究了不同的SCS模式如何调节NK1R +神经元的激活。在胫骨保留神经损伤（SNI-t）后2周，与未受伤小鼠相比，腰脊髓（L4-5）中的神经激肽1受体阳性神经元在后爪受到电测试刺激（TS，3.0 mA，1 Hz）时表现出更大的激活。然后通过放置在L1-2水平硬膜外的双极板电极进行脊髓刺激。短期50 Hz高强度SCS（80%运动阈值[MoT]，10分钟）在未受伤和SNI-t小鼠中均诱导了对NK1R +神经元对TS反应的强烈且持久的抑制。以中等强度（50% MoT）施加30分钟的50 Hz和900 Hz SCS也显著抑制了SNI-t小鼠中的神经元反应。然而，在低强度（20% MoT）下，30分钟的900 Hz SCS仅在未受伤小鼠中诱导了持续的神经元抑制，而在SNI-t小鼠中则没有。总之，10分钟的高强度SCS和30分钟的中等强度SCS均抑制了浅表NK1R +神经元的激活，可能减弱脊髓伤害性传递。此外，NK1R +神经元的体内钙成像为探索神经调节性疼痛疗法抑制疼痛的脊髓神经元机制提供了一种新方法。
