The
pain-depression dyad is becoming widespread in the clinic and is attracting increasing attention. A previous study by our group found that 100-Hz electro-acupuncture (EA), but not 2-, 50- and 2/100-Hz EA, was effective against the
reserpine-induced
pain-depression dyad. This finding is in contrast to the fact that low-frequency EA is commonly used to treat supraspinal-originating diseases. The present study aimed to investigate the mechanism underlying the effects of 100-Hz EA on the
pain-depression dyad. Repeated
reserpine injection was found to induce
allodynia and depressive behaviors in rats. It decreased
5-hydroxytryptamine (5-HT) levels and immunoreactive expressions in the dorsal raphe nucleus (DRN). 100-Hz EA alleviated the
pain-depression dyad and upregulated
5-HT in the DRN of
reserpine-injected rats. Intracerebroventricular injection of
para-chlorophenylalanine, an inhibitor of
5-HT resynthesis, suppressed the upregulation of
5-HT in the DRN by 100-Hz EA and partially counteracted the
analgesic and anti-depressive effects of 100-Hz EA. The present study was the first to demonstrate that
5-HT in the DRN is involved in mediating the
analgesic and anti-depressive effects of 100-Hz EA on the
pain-depression dyad. This finding provided a scientific basis for high-frequency EA as a potential treatment for the
pain-depression dyad.