British journal of anaesthesia · 2025
Propofol inhibits norepinephrine release in vivo at presynaptic varicosities of locus coeruleus neurones in zebrafish larvae.
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Du Wenjie, Hu Yue, Yang Yongxin, Li Jia, Liu Mingjian, Zhang Changmei, Wang Yufan, Xiang Peishan, Yu Qiong, Du Jiulin, Wang Yingwei
Аннотация
BACKGROUND: Understanding the mechanisms by which general anaesthetics induce loss of consciousness remains one of the important scientific challenges in medicine and neuroscience. The locus coeruleus-norepinephrine (LC-NE) system plays important roles in general anaesthesia. Both i.v. and inhalation anaesthetics can reduce NE signalling by suppressing the excitatory synaptic inputs and intrinsic excitability of LC-NE neurones. However, it remains unknown whether anaesthetics can directly target presynaptic sites on LC-NE neurone axons to impair NE release.
METHODS: In vivo whole-cell recording and chemogenetics were used to control the activity of LC-NE neurones in intact larval zebrafish, while in vivo time-lapse imaging was used to examine NE release and Ca2+ influx at individual presynaptic varicosities of the recorded neurones. The G protein-coupled receptor (GPCR) activation-based NE sensor GRABNE2m and the genetically encoded Ca2+ sensor GCaMP6s were used to detect NE release and Ca2+ levels, respectively.
RESULTS: Propofol directly inhibited NE release from individual presynaptic varicosities of LC-NE neurones, because GRABNE2m signals induced by precisely controlled activity of LC-NE neurones were markedly reduced after propofol application. Propofol significantly suppressed presynaptic varicosity Ca2+ activities of LC-NE neurones. These effects were diminished by co-application of picrotoxin, an antagonist of gamma-aminobutyric acid type A receptors, to the area where the varicosities are located. The degree of propofol-induced inhibition varied across individual varicosities but was relatively homogeneous among different brain areas.
CONCLUSIONS: Propofol can directly target the locus coeruleus norepinephrine neurone axons to suppress norepinephrine release at presynaptic varicosities.
METHODS: In vivo whole-cell recording and chemogenetics were used to control the activity of LC-NE neurones in intact larval zebrafish, while in vivo time-lapse imaging was used to examine NE release and Ca2+ influx at individual presynaptic varicosities of the recorded neurones. The G protein-coupled receptor (GPCR) activation-based NE sensor GRABNE2m and the genetically encoded Ca2+ sensor GCaMP6s were used to detect NE release and Ca2+ levels, respectively.
RESULTS: Propofol directly inhibited NE release from individual presynaptic varicosities of LC-NE neurones, because GRABNE2m signals induced by precisely controlled activity of LC-NE neurones were markedly reduced after propofol application. Propofol significantly suppressed presynaptic varicosity Ca2+ activities of LC-NE neurones. These effects were diminished by co-application of picrotoxin, an antagonist of gamma-aminobutyric acid type A receptors, to the area where the varicosities are located. The degree of propofol-induced inhibition varied across individual varicosities but was relatively homogeneous among different brain areas.
CONCLUSIONS: Propofol can directly target the locus coeruleus norepinephrine neurone axons to suppress norepinephrine release at presynaptic varicosities.