Although previous studies have demonstrated that EA treatment with 2 Hz is more effective than 100 Hz for the regulation of supraspinal opioid function in analgesia [29–31], we found that EA with 100 Hz most significantly improved negative behavioral symptoms in the reserpine-induced pain-depression dyad in which 5-HT in supraspinal central nervous system (CNS) plays an important role. Here, HTR5A is linked to depressive disorder.