Paeoniflorin Promotes Non-rapid Eye Movement Sleep via Adenosine A1 Receptors.
Paeoniflorin (PF, C23H28O11), one of the principal active ingredients of Paeonia Radix, exerts depressant effects on the central nervous system. We determined whether PF could modulate sleep behaviors and the mechanisms involved. Electroencephalogram and electromyogram recordings in mice showed that intraperitoneal PF administered at a dose of 25 or 50 mg/kg significantly shortened the sleep latency and increased the amount of non-rapid eye movement (NREM). Immunohistochemical study revealed that PF decreased c-fos expression in the histaminergic tuberomammillary nucleus (TMN). The sleep-promoting effects and changes in c-fos induced by PF were reversed by 8-cyclopentyl-1,3-dimethylxanthine (CPT), an adenosine A1 receptor antagonist, and PF-induced sleep was not observed in adenosine A1 receptor knockout mice. Whole-cell patch clamping in mouse brain slices showed that PF significantly decreased the firing frequency of histaminergic neurons in TMN, which could be completely blocked by CPT. These results indicate that PF increased NREM sleep by inhibiting the histaminergic system via A1 receptors.
Department of Pharmacology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China (C.-R.C., Y.S., Y.-J.L., W.-M.Q., Z.-L.H.); Department of Pharmacology, School of Medical Science, Ningbo University, Ningbo, Zhejiang, People's Republic of China (X.Z.); Department of Neurology, School of Medicine, Boston University, Boston, Massachusetts (J.-F.C.); Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan (Y.Y.).
Chang-Rui
CR
Chen
Department of Pharmacology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China (C.-R.C., Y.S., Y.-J.L., W.-M.Q., Z.-L.H.); Department of Pharmacology, School of Medical Science, Ningbo University, Ningbo, Zhejiang, People's Republic of China (X.Z.); Department of Neurology, School of Medicine, Boston University, Boston, Massachusetts (J.-F.C.); Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan (Y.Y.).
Yu
Y
Sun
Department of Pharmacology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China (C.-R.C., Y.S., Y.-J.L., W.-M.Q., Z.-L.H.); Department of Pharmacology, School of Medical Science, Ningbo University, Ningbo, Zhejiang, People's Republic of China (X.Z.); Department of Neurology, School of Medicine, Boston University, Boston, Massachusetts (J.-F.C.); Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan (Y.Y.).
Yan-Jia
YJ
Luo
Department of Pharmacology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China (C.-R.C., Y.S., Y.-J.L., W.-M.Q., Z.-L.H.); Department of Pharmacology, School of Medical Science, Ningbo University, Ningbo, Zhejiang, People's Republic of China (X.Z.); Department of Neurology, School of Medicine, Boston University, Boston, Massachusetts (J.-F.C.); Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan (Y.Y.).
Xin
X
Zhao
Department of Pharmacology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China (C.-R.C., Y.S., Y.-J.L., W.-M.Q., Z.-L.H.); Department of Pharmacology, School of Medical Science, Ningbo University, Ningbo, Zhejiang, People's Republic of China (X.Z.); Department of Neurology, School of Medicine, Boston University, Boston, Massachusetts (J.-F.C.); Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan (Y.Y.).
Jiang-Fan
JF
Chen
Department of Pharmacology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China (C.-R.C., Y.S., Y.-J.L., W.-M.Q., Z.-L.H.); Department of Pharmacology, School of Medical Science, Ningbo University, Ningbo, Zhejiang, People's Republic of China (X.Z.); Department of Neurology, School of Medicine, Boston University, Boston, Massachusetts (J.-F.C.); Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan (Y.Y.).
Yuchio
Y
Yanagawa
Department of Pharmacology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China (C.-R.C., Y.S., Y.-J.L., W.-M.Q., Z.-L.H.); Department of Pharmacology, School of Medical Science, Ningbo University, Ningbo, Zhejiang, People's Republic of China (X.Z.); Department of Neurology, School of Medicine, Boston University, Boston, Massachusetts (J.-F.C.); Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan (Y.Y.) huangzl@fudan.edu.cn quweimin@fudan.edu.cn.
Wei-Min
WM
Qu
Department of Pharmacology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China (C.-R.C., Y.S., Y.-J.L., W.-M.Q., Z.-L.H.); Department of Pharmacology, School of Medical Science, Ningbo University, Ningbo, Zhejiang, People's Republic of China (X.Z.); Department of Neurology, School of Medicine, Boston University, Boston, Massachusetts (J.-F.C.); Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan (Y.Y.) huangzl@fudan.edu.cn quweimin@fudan.edu.cn.
Zhi-Li
ZL
Huang
D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D005960:Glucosides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006632:Histamine / Q000502:physiology; D007274:Injections, Intraperitoneal; D008297:Male; D008326:Mammillary Bodies / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039821:Monoterpenes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D029596:Paeonia / Q000737:chemistry; D018408:Patch-Clamp Techniques; D043682:Receptor, Adenosine A1 / Q000187:drug effects* / Q000235:genetics; D012890:Sleep / Q000187:drug effects*; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D006027:Glycosides
D002492:Central Nervous System Depressants; D005960:Glucosides; D006632:Histamine; D039821:Monoterpenes; D043682:Receptor, Adenosine A1; D013806:Theophylline; C015423:peoniflorin; D006027:Glycosides; C053907:8-cyclopentyl-1,3-dimethylxanthine