A GABAergic ZI-RVM pathway governs descending modulation of neuropathic pain

The rostral ventromedial medulla (RVM) is a central hub of the descending pain modulatory system, yet the inhibitory circuits that regulate its activity during neuropathic pain remain poorly defined. The zona incerta (ZI), a predominantly GABAergic nucleus in the subthalamic region, has been implicated in nociceptive modulation, but its functional connection to the RVM has not been established. Here, we identify a GABAergic projection from the ZI to the RVM and demonstrate its causal role in neuropathic pain regulation. Using a chronic constriction injury (CCI) model, we show that ZI neurons are selectively activated on the ipsilateral side following nerve injury and project to the ipsilateral RVM. Optogenetic activation of ZI-derived terminals in the RVM significantly alleviated CCI-induced mechanical allodynia, whereas optogenetic inhibition exacerbated pain behaviors. Consistently, chemogenetic excitation of ZI-RVM neurons attenuated hypersensitivity, while chemogenetic silencing had the opposite effect. Together, these findings reveal a novel diencephalic-to-brainstem inhibitory pathway that exerts dynamic control over RVM-mediated descending modulation of neuropathic pain.