Effects Of Inhibition Or Destruction Of Locus Coeruleus Noradrenergic Nerve On Potency Of Volatile Anesthetics In Mice

Objective and background:The mechanisms involved in loss of consciousness,anesthesia maintenance and recovery of consciousness induced by general anesthesia are obviously different.Locus coeruleus（LC）plays an important role in regulating physiological functions such as arousal,attention,stress and so on.Low function of LC is common in clinically aged patients with neurodegenerative diseases.In animal experimental studies,DSP-4,a selective neurotoxin to destroy LC-NE nerve,which is often used to simulate low LC function caused by neurodegenerative diseases in the elderly.Dexmedetomidine（Dex）is a widely usedα2-adrenergic receptor agonist clinically.The mechanism of its function of sedation is believed to be mainly related to the inhibition of LC function.It is not clear whether there is any difference in the effects of damaging LC with DSP-4 and inhibiting LC function by Dex on induction,maintenance and recovery of anesthesia.Purpose of this study was to observe effects of DSP-4 and Dex on minimum alveolar concentration of inhalation anesthesia during induction,maintenance and emergence period,and to observe the change of Electroencephalogram（EEG）.Methods:1.Effects of chronic damage of LC with DSP-4 or acute inhibition with Dexmedetomidine（Dex）intraperitoneal injection on induction,maintenance and emergence of sevoflurane and isoflurane anesthesia in mice.1.1 Effects of DSP-4 and Dex on time to loss of righting reflex(Time_LORR)and recovery of righting reflex(Time_RORR)for sevoflurane and isoflurane anesthesia.Male adult C57 mice were randomly divided into 6 groups to determine Time_LORR and Time_RORR,including the control,DSP-4 and Dex group for sevoflurane and isoflurane respectively.We used a self-made high-throughput gas anesthesia system for mice.In DSP-4 group,a dose of 50mg/kg DSP-4 were injected intraperitoneally 7 days before the test.In Dex group,a dose of 20ug/kg dexmedetomidine was injected intraperitoneally 30minutes before the behavioral test.The control group injected the same dose of saline.We determined Time_LORR and Time_RORR in mice received 1MAC of sevoflurane（2.3%）and isoflurane（1.2%）during 08:00-12:00 am.1.2.Effects of DSP-4 and Dex on MAC_LORR,MAC_RORR and MAC for sevoflurane and isoflurane anesthesia.Male adult C57 mice were randomly divided into 6 groups as above.To test MAC_LORR（the anesthetic dose at which half of the mice lost their righting reflex）,MAC_RORR（the anesthetic dose at which half of the mice recover their righting reflex）and MAC（the anesthetic dose at which half of the mice lost response to noxious stimulation）along with their corresponding 95%confidence intervals,including the control,DSP-4 and Dex group for sevoflurane and isoflurane respectively.The log of volatile anesthetics concentration versus loss of righting reflex,recovery of righting reflex and immobility were fit with nonlinear dose-response curves.2.Effects of DSP-4 and Dex on EEG signals during induction,maintenance and emergence of sevoflurane and isoflurane anesthesia.Male adult c57 mice with prefrontal cortex（PFC）electrode embedding two weeks before the experiment were randomly divided into 6 groups for sevoflurane and isoflurane including the control,DSP-4 and Dex group respectively,and were used for EEG recording and analysis of the anesthesia process including awake,induction,maintenance,and emergence.Results:1.Compared the control group,Time_LORR was not changed in DSP-4 group,but Time_RORRwas significantly delayed.Pretreatment of Dex reduced Time_LORR and delayed Time_RORR to both volatile anesthetics.2.MAC_LORR in DSP-4 group was not significantly different from controls for sevoflurane anesthesia,while MAC_LORR in Dex group was significantly lower compared to controls.DSP-4 and Dex both reduced MAC_RORR and the dose-response curves of RORR of both were left-shifted as compared with that in controls.MAC_LORR in DSP-4 mice was not significantly different from controls for isoflurane anesthesia,while MAC_LORR in Dex group was significantly lower compared to controls.The dose-response curves of RORR in DSP-4 and Dex group were both left-shifted and MAC_RORR of both reduced as compared with that in the control group for isoflurane anesthesia.There was no significant difference for MAC in DSP-4 group compared to the control,while Dex decreased MAC of sevoflurane and isoflurane.3.Compare to the control group,DSP-4 group showed a significant increase of absolute power delta wave of EEG during anesthesia emergence and a significant decrease of absolute power delta wave of EEG during anesthesia maintenance for sevoflurane and isoflurane,while there was no difference during anesthesia induction.Pretreatment of Dex leads to a significant increase absolute power in delta band during anesthesia induction,maintenance and emergence period.Compare to the control group,DSP-4 group showed an increase of burst suppression ratio（BSR）during anesthesia maintenance period,while Dex group showed no significant difference in BSR for sevoflurane and isoflurane anesthesia.Conclusion:1.Damage to LC-NE nerve with DSP-4 mainly increases the burst suppression（BS）of EEG in the maintenance of volatile anesthesia and leads to delayed emergence,which does not affect anesthesia induction.Dexmedetomidine has effects on induction,maintenance and emergence of volatile anesthesia.2.DSP-4 and Dex have different effects on induction,immobility and emergence of volatile anesthetics.The effect of Dex on delayed recovery is related to the inhibition of LC function,while its effect on induction and reduction of MAC has other mechanisms.