Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
Spinal Cord Injury Center, Heidelberg University, Heidelberg, Germany.
FASEB J. 2021 Feb;35(2):e21173. doi: 10.1096/fj.202001775R. Epub 2020 Nov 23.
Neuropathic pain (NP) is a common complication that negatively affects the lives of patients with spinal cord injury (SCI). The disruption in the balance of excitatory and inhibitory neurons in the spinal cord dorsal horn contributes to the development of SCI and induces NP. The calcium-binding protein (CaBP) calbindin-D 28K (CaBP-28K) is highly expressed in excitatory interneurons, and the CaBP parvalbumin (PV) is present in inhibitory neurons in the dorsal horn. To better define the changes in the CaBPs contributing to the development of SCI-induced NP, we examined the changes in CaBP-28K and PV staining density in the lumbar (L4-6) lamina I and II, and their relationship with NP after mild spinal cord contusion injury in mice. We additionally examined the effects of alternate thermal stimulation (ATS). Compared with sham mice, injured animals developed mechanical allodynia in response to light mechanical stimuli and exhibited mechanical hyporesponsiveness to noxious mechanical stimuli. The decreased response latency to heat stimuli and increased response latency to cold stimuli at 7 days post injury suggested that the injured mice developed heat hyperalgesia and cold hypoalgesia, respectively. Temperature preference tests showed significant warm allodynia after injury. Animals that underwent ATS (15-18 and 35-40°C; +5 minutes/stimulation/day; 5 days/week) displayed significant amelioration of heat hyperalgesia, cold hypoalgesia, and warm allodynia after 2 weeks of ATS. In contrast, mechanical sensitivity was not influenced by ATS. Analysis of the CaBP-28K positive signal in L4-6 lamina I and II indicated an increase in staining density after SCI, which was associated with an increase in the number of CaBP-28K-stained L4-6 dorsal root ganglion (DRG) neurons. ATS decreased the CaBP-28K staining density in L4-6 spinal cord and DRG in injured animals, and was significantly and strongly correlated with ATS alleviation of pain behavior. The expression of PV showed no changes in lamina I and II after ATS in SCI animals. Thus, ATS partially decreases the pain behavior after SCI by modulating the changes in CaBP-associated excitatory-inhibitory neurons.
神经病理性疼痛（NP）是一种常见的并发症，会对脊髓损伤（SCI）患者的生活产生负面影响。脊髓背角中兴奋性和抑制性神经元平衡的破坏导致 SCI 的发生，并诱导 NP。钙结合蛋白（CaBP）钙结合蛋白 28K（CaBP-28K）在兴奋性中间神经元中高度表达，而钙结合蛋白 parvalbumin（PV）存在于背角中的抑制性神经元中。为了更好地定义 CaBP 的变化对 SCI 诱导的 NP 的发展的贡献，我们检查了钙结合蛋白-28K 和 PV 染色密度在腰椎（L4-6）I 和 II 层中的变化，以及它们与轻度脊髓挫伤损伤后 NP 的关系在小鼠中。我们还检查了交替热刺激（ATS）的影响。与假手术小鼠相比，受伤动物对轻机械刺激表现出机械性痛觉过敏，并对有害机械刺激表现出机械性反应迟钝。受伤后 7 天，对热刺激的反应潜伏期缩短，对冷刺激的反应潜伏期延长，表明受伤小鼠分别发展为热痛觉过敏和冷痛觉过敏。温度偏好测试显示受伤后出现明显的温热性痛觉过敏。接受 ATS（15-18 和 35-40°C；+5 分钟/刺激/天；每周 5 天）的动物在 ATS 后 2 周显示出对热痛觉过敏、冷痛觉过敏和温热性痛觉过敏的显著改善。相比之下，机械敏感性不受 ATS 的影响。对 L4-6 层 I 和 II 中 CaBP-28K 阳性信号的分析表明，SCI 后染色密度增加，这与 CaBP-28K 染色的 L4-6 背根神经节（DRG）神经元数量增加有关。ATS 降低了受伤动物 L4-6 脊髓和 DRG 中的 CaBP-28K 染色密度，与 ATS 缓解疼痛行为呈显著和强烈相关。在 SCI 动物中，ATS 后 I 和 II 层的 PV 表达没有变化。因此，ATS 通过调节与 CaBP 相关的兴奋性抑制性神经元的变化，部分减轻 SCI 后的疼痛行为。
