D2 receptor activation relieves pain hypersensitivity by inhibiting superficial dorsal horn neurons in parkinsonian mice

Authors: Dong-liang Tang1, Yi-wen Luan1, Chun-yi Zhou1,2, Cheng Xiao1,2
1 School of Anesthesiology, Xuzhou Medical University, Xuzhou 221004, China
2 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou 221004, China
Correspondence to: Chun-yi Zhou:, Cheng Xiao:,
DOI: 10.1038/s41401-020-0433-3
Received: 24 February 2020
Accepted: 8 May 2020
Advance online: 21 July 2020


Chronic pain is a common and undertreated nonmotor symptom in Parkinson’s disease (PD). Although chronic pain is improved by L-dopa in some PD patients, the underlying mechanisms remain unclear. In this study, we established PD mice by unilateral microinjection of 6-OHDA in the medial forebrain bundle to investigate the contribution of spinal cord dopamine receptors to parkinsonian pain hypersensitivity. The von Frey filament tests and thermal pain tests revealed that these PD mice displayed decreased nociceptive thresholds in both hindpaws; intrathecal injection of L-dopa or apomorphine significantly increased the mechanical and thermal nociceptive thresholds, and the analgesic effect was mimicked by ropinirole (a D2 receptor agonist), but not SKF38393 (a D1/D5 receptor agonist), and blocked by sulpiride (a D2 receptor antagonist), but not SKF83566 (a D1/D5 receptor antagonist). Whole-cell recordings in lumber spinal cord slices showed that superficial dorsal horn (SDH) neurons in PD mice exhibited hyperexcitability, including more depolarized resting membrane potentials and more action potentials evoked by depolarizing current steps, which were mitigated by ropinirole. Furthermore, ropinirole inhibited the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in SDH neurons more strongly in PD mice than in control mice. However, sulpiride caused less disinhibition of sEPSCs in PD mice than in control mice. Taken together, our data reveal that pain hypersensitivity in PD mice is associated with hyperexcitability of SDH neurons, and both events are reversed by activation of spinal D2 receptors. Therefore, spinal D2 receptors can be promising therapeutic targets for the treatment of PD pain.
Keywords: Parkinson’s disease; pain hypersensitivity; spinal cord; dorsal horn neuron; hyperexcitability; dopamine D2 receptor; intrathecal administration; whole-cell recording

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