• Xiaopeng Zhou, Eric Ichesco, Andrew Q Pucka, Ziyue Liu, Andrew Rw O'Brien, Steven E Harte, Richard E Harris, and Ying Wang.
• School of Health Sciences, Purdue University, West Lafayette, IN, USA.
• J Pain. 2024 Nov 28; 27: 104743104743.

AbstractSickle 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 (1H-MRS) was conducted to measure levels of Glx and other brain metabolites using a single voxel (size: 2×3×3 cm3) 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.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

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