This study identifies a nigro-subthalamic circuit (SNrGABA → SNcDA → STN) that selectively modulates contralateral mechanical (but not thermal) pain in mice and shows that STN D2 receptor activation alleviates mechanical hyperalgesia in both neuropathic and Parkinsonian models.

By defining a specific circuit and receptor (STN D2) that can be targeted to reduce Parkinsonian and neuropathic mechanical pain, the work provides an actionable mechanistic target with translational potential for repurposing D2-directed therapies or developing focal neuromodulation strategies for…

Dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) degenerate in Parkinson's disease (PD). Although pain is a common non-motor symptom in PD, it remains unclear whether and how degeneration of SNc DA neurons contributes to hyperalgesia. In the present study, we revealed a nigro-subthalamic DA circuit, composed of a subset of SNc DA neurons, the SNc DA projection to the subthalamic nucleus (STN), and the downstream STN neurons. These components regulate mechanical, but not thermal, pain threshold on the contralateral side, exhibiting distinct responses to mechanical and thermal stimuli which varied in neuropathic pain and Parkinsonian mice. D2-, but not D1-like, dopamine receptors in the STN were involved in these processes, and their activation mitigated mechanical hyperalgesia in both neuropathic pain and Parkinsonian mice. The GABAergic neurons in the substantia nigra pars reticulata (SNr) responded to pain stimulation and facilitated pain responses in SNc DA neurons. Thus, the SNrGABA-SNcDA-STN pathway is involved in the modulation and processing of pain in both physiological and chronic pain states and may be a potential therapeutic target for both neuropathic and Parkinsonian pain.