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

• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（2）
• 所属期刊栏目: Article Neuropharmacology
• 页码范围: 189-198
• 页数: 10页
• 语种: 英文
• DOI: 10.1038/S41401-020-0433-3

摘要

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.