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

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, 10 12 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.