Dopamine D 1 and D 2 receptors mediate analgesic and hypnotic effects of l -tetrahydropalmatine in a mouse neuropathic pain model

Rationale Levo-tetrahydropalmatine ( l -THP), an active ingredient of Corydalis yanhusuo , has been reported to be a partial agonist for dopamine D 1 receptors (D 1 R) and an antagonist for D 2 R. Although it has been safely used clinically in China for decades as an analgesic with sedative/hypnotic properties, there are few studies that address the mechanisms by which l -THP exerts its beneficial effects in chronic pain-induced sleep disturbance. Objectives To investigate the effects and mechanisms of l -THP on sleep disturbance in a neuropathic pain-like condition. Methods A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSNL) was employed. The antinociceptive and hypnotic effects of l -THP were evaluated by measurement of mechanical allodynia, thermal hyperalgesia, and electroencephalogram (EEG) recordings in PSNL mice. Pharmacological approaches and c-Fos expression were used to clarify the mechanisms of l -THP. Results Intraperitoneal injection of l -THP at 5 and 10 mg/kg not only significantly increased the mechanical threshold by 134.4% and 174.8%, and prolonged the thermal latency by 49.4% and 69.2%, but also increased non-rapid eye movement sleep by 17.5% and 29.6%, and decreased sleep fragmentation in PSNL mice, compared with the vehicle control. Moreover, the antinociceptive effect of l -THP was prevented by D 1 R antagonist SCH23390 or D 2 R agonist quinpirole; meanwhile, the hypnotic effect of l -THP was blocked by quinpirole rather than by SCH23390. Immunohistochemistry demonstrated that l -THP inhibited c-Fos overexpression induced by PSNL in the cingulate cortex and the periaqueductal gray. Conclusions These findings indicated that l -THP exerted analgesic effects by agonism D 1 R and antagonism D 2 R, and the antagonism of D 2 R mediated the hypnotic effect of l -THP in PSNL mice.