Neuropeptide S Reduced Propofol-and Ketamine-Induced Slow-Wave-Sleep Through Activation Of Its Receptor In Rats

A number of literatures reported that general anesthesia and natural sleep share many obvious similarities. According to some imaging studies, obvious parallels were shown between the anaesthetized brain and the brain during slow wave sleep (SWS). More strikingly, most anesthetics produce EEG patterns that are reminiscent of both spindle and delta waves, the EEG landmarks of falling asleep and deep, dreamless SWS, respectively. Several nuclei have been recognized as important loci involved in regulation of sleep and anesthesia, for example, the hypothalamic ventrolateral preoptic nucleus (VLPO) and the posterior hypothalamic HAergic and orexinergic neurons. Clinically relevant intravenous anesthetics are grouped into two types, i.e. GABAAtype (propofol) and NMDA type (ketamine). Neuropeptide S and its cognate receptor (NPS-NPSR) system is considered as a newly identified sleep-waking regulation system. Stimulatory peptide such as orexin was used to reduce anesthesia duration. Using NPS and its cognate receptor antagonist [D-Val5]NPS, the present study was designed to detect the effects of NPS-NPSR system on both GABAA and NMDA types of anesthetics-induced sleep-wake profiles and the characteristics of EEG power spectrum.Methods:EEG and EMG were employed to evaluate the effect of NPS (1,2,5nmol) ICV on the sleep-wake profile in PT or K.T rats. LORR assay was applied to record the effects of NPS ICV on anesthesia time in mice.[D-Val5]NPS. a potent NPSR antagonist was used to investigate whether NPS-NPSR system impacts the SWS or LORR induced by anesthetics.7days after surgery, on the experiment day, NPS or saline was injected ICV,5minutes later, ketamine or propofol was injected IP. A12-h sleep-wake polysomnogram was recorded and analyzed by spike2software. LORR and induction time was recorded in anesthetic-treated mice. Data were expressed as means±SEM. For total amount of sleep-wake stages and their mean episode number and duration, LORR and induction time, different parameters were analyzed using one-way analysis of variance (ANOVA) and post hoc Fisher’s least significant difference (LSD) test. The criterion for significance was set at p<0.05.Results:1. Compared with saline, ICV injection of1nmol NPS reduced LORR time by36.8%and46.1%respectively in PT (100mg/kg,2285±290s vs.1504±152s, p<0.05) and KT mice (100mg/kg,1516±139s vs.817±206s, p<0.05), but not the induction time, i.e.298±47s vs.240±63s, p>0.05in PT mice and129±15s vs.96±15s, p>0.05in KT mice. When co-injection with1nmol NPS,20nmol [D-val5] NPS reverse its effects to as with saline (p>0.05), but alone did not prolong LORR time in PT and KT mice.2. In PT rats, ICV injection of saline produced about40min SWS characterized by increased EEG delta activity(0.5-4.0Hz). Compared with saline, ICV injection of1-2nmol NPS dose dependently reduced SWS and EEG delta activity by12.48%(28.35±2.23min vs.40.83±2.70min, p<0.05) and13.92%(26.92±4.21min vs.40.83±2.70min, p<0.05), but did not change the SWS latency.1-2nmol NPS reduced mean SWS duration (7.97±1.35and7.94±1.18min vs.14.36±2.96min in saline, p<0.05). but did not change the episode number.3. In KT rats, ICV injection of saline produced about41min SWS characterized by increased EEG delta activity(0.5-4Hz) and theta activity (4.5-9.0Hz). Compared with saline, ICV injection of1-5nmol dose dependently reduced SWS and EEG delta activity by23.37%(31.42±2.59min vs.41.00±3.91min, p<0.05) and36.93%(25.85±4.56min vs.41.00±3.91min, p<0.05), but did not change the SWS latency.1-2nmol NPS reduced mean SWS duration (9.31±1.08and9.80±1.01min vs.15.56±2.63min in saline. p<0.05). but did not change the episode number.4. NPS reduced SWS in the first hour following injection in PT and KT rats, but did not change the12-h sleep-wake states profiles.5. When co-injection with I nmol NPS,20nmol [D-Val5] NPS reverse its arousal promoting effects to as with saline (p>0.05), but alone did not prolong SWS time in PT and KT rats.Conclusions:NPS reduced LORR time in PT and KT mice and SWS in PT and KT rats, but not the induction time of both anesthetics. NPS reduced EEG delta activity in PT rats, and suppressed EEG delta activity but increased theta activity in KT rats. NPS reduced SWS through reduction of mean duration not the episode number. NPS antagonist could reverse the arousal promoting effect of exogenous NPS. NPS significantly increased wakefulness and reduced SWS induced by anesthesia via selective stimulation of the NPSR and subsequent wakefulness-promoting pathways.