A GABAergic Projection from the Zona Incerta to the Rostral Ventromedial Medulla Modulates Descending Control of Neuropathic Pain

Background: 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. Methods: A chronic constriction injury (CCI) model was used to induce neuropathic pain. Neuronal activation and circuit connectivity were examined using anatomical tracing and activity mapping. Optogenetic and chemogenetic approaches were employed to selectively manipulate ZI-derived GABAergic projections to the RVM, and mechanical sensitivity was assessed using behavioral assays. Results: CCI selectively activated ZI neurons on the ipsilateral side of nerve injury (p = 0.0452), which projected to the ipsilateral RVM. Optogenetic activation of ZI-derived terminals in the RVM significantly alleviated CCI-induced mechanical allodynia (p = 0.0038), whereas optogenetic inhibition exacerbated pain behaviors (p = 0.0183). Consistently, chemogenetic excitation of ZI–RVM neurons attenuated hypersensitivity (p < 0.0001), while chemogenetic silencing had the opposite effect (p = 0.0015). Conclusions: These findings reveal a novel diencephalic-to-brainstem inhibitory pathway that exerts dynamic control over RVM-mediated descending modulation of neuropathic pain.