Dopamine D1 and D2 receptors mediate analgesic and hypnotic effects of l-tetrahydropalmatine in a mouse neuropathic pain model
Dopamine D1 and D2 receptors mediate analgesic and hypnotic effects of l-tetrahydropalmatine in a mouse neuropathic pain model
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多巴胺 D-1 和 D-2 受体介导左旋四氢延胡索乙素在小鼠神经病理性疼痛模型中的镇痛和催眠作用
DOI：
10.1007/s00213-019-05275-3
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发表时间：
2019-11-01
影响因子：
3.4
通讯作者：
Huang, Zhi-Li
中科院分区：
文献类型：
--
作者：
Liu, Yuan-Yuan;Wang, Tian-Xiao;Huang, Zhi-Li
左旋四氢巴马汀（Levo-tetrahydropalmatine，l-THP）是延胡索的有效成分，是多巴胺D-1受体（D1 R）的部分激动剂和D2 R的拮抗剂。虽然它已被安全地用于临床几十年来在中国作为一种镇痛药的镇静/催眠特性，有很少的研究，解决的机制，l-THP发挥其有益的影响，在慢性疼痛引起的睡眠障碍。目的探讨左旋吡柔比星（l-THP）对神经病理痛样睡眠障碍的影响及其机制。方法采用部分坐骨神经结扎（PSNL）法建立小鼠慢性神经病理性疼痛模型。通过测量PSNL小鼠的机械异常性疼痛、热痛觉过敏和脑电图（EEG）记录来评价l-THP的抗伤害性和催眠作用。药理学方法和c-Fos表达被用来阐明l-THP的机制。结果腹腔注射l-THP 5和10 mg/kg，与对照组相比，PSNL小鼠机械阈值分别增加134.4%和174.8%，热潜伏期分别延长49.4%和69.2%，非快动眼睡眠分别增加17.5%和29.6%，睡眠碎片减少。此外，l-THP的抗伤害作用被D1受体拮抗剂SCH 23390或D2受体激动剂quinpirole阻断;同时，l-THP的催眠作用被quinpirole阻断，而不是被SCH 23390阻断。免疫组化结果显示，l-THP可抑制PSNL诱导的扣带回皮质和导水管周围灰质c-Fos的过度表达。结论l-THP通过激动D1 R和拮抗D2 R发挥镇痛作用，而D2 R的拮抗作用是l-THP催眠作用的重要机制。
Rationale Levo-tetrahydropalmatine (l-THP), an active ingredient of Corydalis yanhusuo, has been reported to be a partial agonist for dopamine D-1 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. 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 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. Conclusions 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.