Dopamine D1 and D2 receptors mediate analgesic and hypnotic effects of l-tetrahydropalmatine in a mouse neuropathic pain model
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Levo-tetrahydropalmatine (l-THP), an active ingredient of Corydalis yanhusuo, has been reported to be a partial agonist for dopamine D1 receptors (D1R) and an antagonist for D2R. 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.
To investigate the effects and mechanisms of l-THP on sleep disturbance in a neuropathic pain-like condition.
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.
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 D1R antagonist SCH23390 or D2R 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.
These findings indicated that l-THP exerted analgesic effects by agonism D1R and antagonism D2R, and the antagonism of D2R mediated the hypnotic effect of l-THP in PSNL mice.
KeywordsLevo-tetrahydropalmatine Sleep disturbance Neuropathic pain Dopamine receptor c-Fos
This manuscript is dedicated to the late Dr.Guo-Zhang Jin to acknowledge his many scientific contributions to dopamine studies. This work was supported in part by grants-in-aid for scientific research from the National Natural Science Foundation of China (Grant No. 31530035, 81420108015 to Zhi-Li Huang, Grant No. 31671099, 31871072 to Wei-Min Qu); the National Basic Research Program of China (Grant No. 2015CB856401 to Zhi-Li Huang); Program for Shanghai Outstanding Academic Leaders (to Zhi-Li Huang); and the Shanghai Committee of Science and Technology (Grant No. 17ZR1402000 to Yuan-Yuan Liu).
Compliance with ethical standards
Experimental protocols were approved by the Committee on the Ethics of Animal Experiments of Fudan University Shanghai Medical College and performed in accordance with ARRIVE guidelines. Every effort was made to minimize the number of animals used and any pain or discomfort experienced by the mice.
Conflict of interest
The authors declare that they have no conflicts of interest.
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