EXPRESS: The enhanced analgesic effects of electroacupuncture and repetitive transcranial magnetic stimulation on visceral pain via ventral lateral septal nucleus

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized primarily by chronic visceral pain, with a complex pathogenesis and limited efficacy of current therapeutic interventions. Growing evidence indicates that electroacupuncture (EA) and repetitive transcranial magnetic stimulation (rTMS) exert significant analgesic effects on visceral pain. However, the underlying neural circuit mechanisms remain poorly understood. In this study, the ventral part of the lateral septal nucleus (LSV) was identified as a critical brain region mediating the analgesic effects of EA and rTMS in a mouse model of visceral pain. Visceral nociceptive stimulation significantly increased c-Fos expression in the LSV, predominantly within glutamatergic neurons. Optogenetic inhibition of LSV glutamatergic neurons attenuated visceral pain, whereas their activation exacerbated pain-related behaviors. Both EA and rTMS individually reduced visceral pain-induced c-Fos expression and alleviated pain behaviors, with the combined EA+rTMS treatment producing a more pronounced analgesic effect than either treatment alone. Moreover, fiber photometry recordings demonstrated that EA and rTMS decreased glutamate release and concurrently increased cannabinoid signaling in the LSV, suggesting that these interventions modulate neurotransmitter dynamics to regulate neuronal excitability. In summary, our findings highlight the pivotal role of LSV glutamatergic neurons in the modulation of visceral pain. EA and rTMS exert their therapeutic effects by regulating glutamate and cannabinoid release within this circuit. These insights provide a foundation for developing targeted neuromodulatory strategies for the treatment of chronic visceral pain.