Targeting the hypothalamic a11 nucleus to treat parkinsonian-like nociceptive impairments

Pain is a common non-motor symptom in Parkinson's disease (PD), yet treatment options remain limited due to incomplete understanding of underlying mechanisms. Using the 6-hydroxydopamine (6-OHDA) rat model, we combined pharmacological, behavioural, chemogenetic, electrophysiological, and immunohistochemical approaches to investigate dopaminergic modulation of nociception by the hypothalamic A11 projecting to the dorsal horn of the spinal cord (DHSC). We demonstrate that A11 dopaminergic neurons are the sole source of dopamine in the DHSC. Activation of both D1 and D2 receptors alleviated mechanical allodynia, while only D2 receptor stimulation improved thermal hyperalgesia and normalized wide dynamic range (WDR) neuron hyperexcitability. Selective chemogenetic activation of the A11-DHSC pathway reduced nociceptive hypersensitivity and improved WDR neuronal function in 6-OHDA rats. These findings establish a critical role of spinal dopaminergic signaling in PD-related pain and highlight the A11 region as a potential therapeutic target for pain management in PD.