Oxytocinergic neurons in the paraventricular nucleus mediate the analgesic effect of electroacupuncture in inflammatory pain

Abstract Background Electroacupuncture (EA) is a well-established and effective analgesic intervention, particularly for inflammatory pain; however, the analgesic effect of EA is closely related to the stimulation frequency, amplitude, and acupoint. The underlying neural mechanisms remain incompletely understood. This study aimed to identify the central neural projections responsible for EA-induced analgesia and to investigate the mechanisms underlying its frequency-specific effects. Methods In this study, we utilized a mouse model of carrageenan (CGN)-induced inflammatory pain to explore the analgesic effects of EA. In vivo fiber photometry and immunofluorescence were employed to monitor the activity of oxytocinergic neurons in the paraventricular nucleus (PVN). The role of neuronal activity in EA-induced analgesia was assessed through chemogenetic and pharmacological approaches. Results We demonstrated that specific activation of PVN oxytocinergic neurons significantly alleviated pain behaviors in the inflammatory pain model mice. EA stimulation of the Stomach meridian 36 (ST36) activated PVN oxytocinergic neurons and exerted an antinociceptive effect in a frequency-dependent manner. Specifically, lower frequency EA stimulation induced more significant PVN oxytocinergic neuronal activity and analgesic effect, while higher frequency EA stimulation did not show significant neuronal activation or pain relief. Chemogenetic silencing of PVN oxytocinergic neurons completely abolished EA-induced analgesia. Additionally, we identified that oxytocinergic projections from the PVN to the arcuate nucleus (ARC) were activated only under lower frequency EA stimulation, while higher frequency EA stimulation failed to exert this effect. What’s more, locally blocking the target of oxytocin in the ARC significantly attenuated the analgesic effect of EA. Conclusions Our findings highlight the critical role of PVN oxytocinergic neurons in mediating the frequency-specific analgesic effects of EA, which provide important evidence for parameter selection in clinical EA treatment for pain.