Insomnia is a common disorder seen in nearly 30%-35% of the general population worldwide, with a range of 10%-15% being assessed as moderate to severe disorders.Symptoms of insomnia include poor sleep quality, difficulty in falling a sleep, frequent awakenings during the night and early morning a wakenings.Insomnia give rise to fatigue, irritability, impaired concentration and reduced alertness, causing serious impact on the quality of life of affected individuals.Current pharmacologi cal treatment of insomnia involves the use of sedative-hypnotic benzodiazepines (BZ) and non-benzodiazepine drugs (Zdrugs).Z-drugs are the first line of management followed by BZ, amitryptiline and antihistamines.Insomnia could be effec tively treated by the Z-drugs, such as zolpidem and the BZ, but their multiple adverse effects hamper their application.Paeoni florin { PF, 5 beta-[(Benzoyloxy) methyl] tetrahydro-5-hydroxy2-methyl-2, 5-methano-lH-3, 4-dioxacyclobuta [cd] pentalen1 alpha(2H)-yl-beta-D-glucopyranoside, C23 H2s O11 | is one of the principal active ingredients of Paeonia Radix.PF possesses inhibitory effects in the nervous system, such as suppress spike discharges and analgesic effect.These observations indicate that PF might have a potent sleep promoting effect.The aim of this study was to determine whether PF could modulate sleep behav iors by recording EEG and electromyogram in mice.The results showed that PF 25 and 50 mg·kg-1 could significantly shorten the sleep latency;increase the amount of non-rapid eye move ment (non-REM, NREM) for 3 h, with an increase in the num ber of NREM and REM sleep episodes.PF 25 and 50 mg·kg-1increased the number of bouts of wakefulness but decreased their duration.On the other hand, PF increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness.However, PF had no effect on the amount of REM sleep.Immunohistochemical study showed that PF increased c-Fos expression in the neurons of ventrolateral preoptic area (VLPO), a sleep center in the anterior hypothala mus, and decreased c-Fos expression in the arousal tuberomam millary nucleus (TMN), which was located in the caudolateral hypothalamus.The sleep-promoting effects and changes in c-fos induced by PF were reversed by CPT, an antagonist at the aden osine A1 R.We found a high degree of colocalization between histaminergic and gabaergic neurons in GAD 67-GFP mice TMN.Then we use GAD 67-GFP mice to help indentify histaminergic neurons.PF inhibited histaminergic neurons in the TMN by whole-cell patch clamping in the brain slice, CPT totally blocked the histaminergic neurons inactivation induced by PF.These re sults indicate that PF increased NREM and REM sleep by inhibi ting the histaminergic system via A1R, suggesting its potential application for the treatment of insomnia.