Elevated posterior insula glutamate in patients with sickle cell disease

Xiaopeng Zhou; Eric Ichesco; Andrew Q Pucka; Ziyue Liu; Andrew Rw O'Brien; Steven E Harte; Richard E Harris; Ying Wang

doi:10.1016/j.jpain.2024.104743

Elevated posterior insula glutamate in patients with sickle cell disease

J Pain. 2024 Nov 28:27:104743. doi: 10.1016/j.jpain.2024.104743. Online ahead of print.

Authors

Xiaopeng Zhou¹, Eric Ichesco², Andrew Q Pucka³, Ziyue Liu⁴, Andrew Rw O'Brien⁵, Steven E Harte², Richard E Harris⁶, Ying Wang⁷

Affiliations

¹ School of Health Sciences, Purdue University, West Lafayette, IN, USA.
² Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA.
³ Department of Anesthesia, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, USA; Susan Samueli Integrative Health Institute, School of Medicine, University of California at Irvine, Irvine, CA, USA; Department of Anesthesiology and Perioperative Care, School of Medicine, University of California at Irvine, Irvine, CA, USA.
⁷ Department of Anesthesia, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: ywa12@iu.edu.

PMID: 39615812
DOI: 10.1016/j.jpain.2024.104743

Abstract

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 (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.

Keywords: (1)H-MRS; Brain metabolites; Glutamate; Pain; Sickle cell disease; Vaso-occlusive crisis.