ROSTRAL VENTROMEDIAL MEDULLA (RVM) D2R-EXPRESSING NEURONS ACTS AS A NOCICEPTIVE RELAY BETWEEN BASAL GANGLIA AND SPINAL CORD

Parkinson’s disease (PD) is a neurodegenerative disorder marked by the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). While this neuronal loss drives the hallmark motor symptoms of PD, it also contributes to multiple non-motor symptoms, including heightened pain sensitivity. In previous work using a mouse model of PD, we demonstrated that pain hypersensitivity arises from an overactivation of spinally projecting serotoninergic (5-HT) neurons in the RVM. This overactivation is associated with an increase in excitatory inputs to these neurons. To further elucidate the relationship between dopamine depletion and 5-HT neuron activity, we investigated the anatomical and functional connections between SNc DA neurons and 5-HT RVM neurons in a physiological context. Our findings reveal that while SNc DA neurons project to the RVM, they do not directly synapse onto 5-HT neurons, nor do 5-HT neurons express D1-like or D2-like receptors (D2R). Instead, we identified a population of RVM neurons (primarily glutamatergic) that express D2R and project locally to 5-HT neurons. Using fiber photometry and optogenetic techniques, we observed that these D2R-expressing neurons respond to nociceptive stimuli and, when strongly activated, induce mechanical and thermal cold allodynia. Given that D2R is a Gi-coupled receptor and dopamine projections are diminished in PD models, we hypothesize that the disinhibition of D2R-expressing neurons in the RVM leads to increased activity of 5-HT neurons. This alteration in the network linking midbrain dopamine, D2R, and 5-HT neurons in the RVM may underlie the pain hypersensitivity observed in Parkinson’s disease.