Terahertz Wave Alleviates Comorbidity Anxiety in Pain by Reducing the Binding Capacity of Nanostructured Glutamate Molecules to GluA2

Zihua Song; Yuankun Sun; Pan Liu; Hao Ruan; Yuanyuan He; Junkai Yin; Chun Xiao; Jing Ma; Yun Yu; Shaomeng Wang; Yubin Gong; Z W Lin; Zhi Zhang; Chao Chang; Maojun Yang

doi:10.34133/research.0535

Terahertz Wave Alleviates Comorbidity Anxiety in Pain by Reducing the Binding Capacity of Nanostructured Glutamate Molecules to GluA2

Research (Wash D C). 2024 Dec 11:7:0535. doi: 10.34133/research.0535. eCollection 2024.

Authors

Zihua Song¹, Yuankun Sun², Pan Liu¹, Hao Ruan¹, Yuanyuan He³, Junkai Yin¹, Chun Xiao⁴, Jing Ma¹, Yun Yu^{1

5}, Shaomeng Wang², Yubin Gong², Z W Lin¹, Zhi Zhang⁶, Chao Chang^{1

7}, Maojun Yang⁴

Affiliations

¹ Innovation Laboratory of Terahertz Biophysics, National Innovation Institute of Defense Technology, Beijing 100071, China.
² School of Electronic Science and Engineering, University of Electronic Science and Technology of China, Chengdu 611731, China.
³ School of Safety Engineering, North China Institute of Science and Technology, Hebei 065201, China.
⁴ School of Life Sciences, Tsinghua University, Beijing 100081, China.
⁵ School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
⁶ Division of Life Sciences and Medicine, Department of Anesthesiology, the First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China.
⁷ School of Physics, Peking University, Beijing 100081, China.

Abstract

Comorbid anxiety in chronic pain is clinically common, with a comorbidity rate of over 50%. The main treatments are based on pharmacological, interventional, and implantable approaches, which have limited efficacy and carry a risk of side effects. Here, we report a terahertz (THz, 10¹² Hz) wave stimulation (THS) technique, which exerts nonthermal, long-term modulatory effects on neuronal activity by reducing the binding between nano-sized glutamate molecules and GluA2, leading to the relief of pain and comorbid anxiety-like behaviors in mice. In mice with co-occurring anxiety and chronic pain induced by complete Freund's adjuvant (CFA) injection, hyperactivity was observed in glutamatergic neurons in the anterior cingulate cortex (ACC^Glu). Using whole-cell recording in ACC slices, we demonstrated that THS (34 THz) effectively inhibited the excitability of ACC^Glu. Moreover, molecular dynamics simulations showed that THS reduced the number of hydrogen bonds bound between glutamate molecules and GluA2. Furthermore, THS target to the ACC in CFA-treatment mice suppressed ACC^Glu hyperactivity and, as a result, alleviated pain and anxiety-like behaviors. Consistently, inhibition of ACC^Glu hyperactivity by chemogenetics mimics THS-induced antinociceptive and antianxiety behavior. Together, our study provides evidence for THS as an intervention technique for modulating neuronal activity and a viable clinical treatment strategy for pain and comorbid anxiety.