Zhou Xiaopeng, Ichesco Eric, Pucka Andrew Q, Liu Ziyue, O'Brien Andrew Rw, Harte Steven E, Harris Richard E, Wang Ying
School of Health Sciences, Purdue University, West Lafayette, IN, USA.
Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA.
J Pain. 2025 Feb;27:104743. doi: 10.1016/j.jpain.2024.104743. Epub 2024 Nov 28.
Sickle cell disease (SCD) is an inherited hemolytic disorder accompanied by chronic pain and recurrent acute painful episodes known as vaso-occlusive crises (VOCs). Increased Glx (glutamate+glutamine) and lowered GABA concentration have been reported in the insula of patients with fibromyalgia, a nociplastic chronic pain condition, and may affect the pathophysiology of pain-related syndromes.Therefore, proton magnetic resonance spectroscopy (H-MRS) was conducted to measure levels of Glx and other brain metabolites using a single voxel (size: 2×3×3 cm) in the right posterior insula cortex (PIC) in 17 individuals with SCD and 17 ethnicity-, age- and sex-matched healthy controls (HCs). The frequency of VOCs in the preceding 12 months was recorded. The concentration of Glx (p=0.019) and the ratio of Glx to tCr (total creatine, p=0.035) in the PIC were significantly higher in patients with SCD as compared to matched HCs (n=17). Secondary analyses with the unpaired full sample of 24 SCD also showed a significantly higher level of Glx/tCr than HCs (n=19), with a positive correlation between the level of Glx/tCr and the number of VOCs (p=0.034, r=0.476), as well as a negative correlation between Glx and sensory sensitivity assessed by tonic pressure pain in gastrocnemius area of the non-dominant leg (p=0.040, r=-0.462). The unpaired full sample additionally revealed a significant difference in sensory sensitivity (p=0.050). Altered metabolites such as GABA and myo-inositol were also observed between SCD and HCs. These results suggest that elevated excitatory neurotransmission in the insula might contribute to nociplastic pain in SCD. PERSPECTIVE: Our work highlighted the innovative finding of elevated levels of the excitatory neurotransmitter glutamate with glutamine in patients with SCD compared to healthy controls. The positive relationship between Glx/tCr and the frequency of VOCs suggests that an excitatory brain neurotransmitter imbalance may be involved in VOCs.
镰状细胞病（SCD）是一种遗传性溶血性疾病，伴有慢性疼痛和反复发作的急性疼痛发作，即血管阻塞性危机（VOCs）。在纤维肌痛（一种神经可塑性慢性疼痛病症）患者的脑岛中，已报告谷氨酸盐+谷氨酰胺（Glx）增加而γ-氨基丁酸（GABA）浓度降低，这可能会影响疼痛相关综合征的病理生理学。因此，进行了质子磁共振波谱（H-MRS），以使用单一体素（大小：2×3×3 cm）测量17名SCD患者和17名种族、年龄和性别匹配的健康对照者（HCs）右侧脑岛后皮质（PIC）中的Glx和其他脑代谢物水平。记录了前12个月内VOCs的发生频率。与匹配的HCs（n = 17）相比，SCD患者PIC中的Glx浓度（p = 0.019）以及Glx与总肌酸（tCr）的比率（p = 0.035）显著更高。对24名SCD患者的未配对全样本进行的二次分析也显示，Glx/tCr水平显著高于HCs（n = 19），Glx/tCr水平与VOCs数量呈正相关（p = 0.034，r = 0.476），并且Glx与通过非优势腿腓肠肌区域的强直压力疼痛评估的感觉敏感性呈负相关（p = 0.040，r = -0.462）。未配对全样本还显示感觉敏感性存在显著差异（p = 0.050）。在SCD患者和HCs之间还观察到了GABA和肌醇等代谢物的变化。这些结果表明，脑岛中兴奋性神经传递的升高可能导致SCD中的神经可塑性疼痛。观点：我们的研究突出了一个创新性发现，即与健康对照者相比，SCD患者中兴奋性神经递质谷氨酸与谷氨酰胺的水平升高。Glx/tCr与VOCs频率之间的正相关表明，兴奋性脑内神经递质失衡可能与VOCs有关。
