Hypnotic Actions Of Local Anesthetics In Mice

PartⅠ:Background:Systemic administration of local anaesthetics is well known for its beneficiary properties at peri-operative and its ability in an anaesthetic-sparing effect, as it has been seen to reduce MAC of volatile anaesthetic in some animal studies, and decrease the requirement of intravenous propofol. These actions are generally considered to reflect central systemic depressive actions of local anesthetics, although its detailed mechanism of action is not kown.In this study, we investigated the effect of Central Nervous System (CNS) excitability in mice with different local anaesthetics and determine its effect using LORR (Loss of Righting Reflex).Methods:We measured the duration and latency to regain the righting reflex of C57BL/6mice, following tail vein intravenous injection of incrementing local anesthetic (5-25mg/kg of lidocaine). Because the blockade of voltage-gated sodium channels by local anesthetics represents the main mechanism for inhibition of action potential propagation, inhibition of sodium channels by local anesthetics was believed to play an important role in producing local anesthetics systemic actions, we also observed the effects of sodium channel blocker (TTX,3and6μg/kg intraperitoneal) on LORR action of local anesthetics.Results:Using the LORR, our results revealed that all local anesthetics produce direct hypnotic action in mice in a dose dependent manner. Lidocaine induced a LORR in mice with a half-maximum concentration (Ec50) of12.5mg/kg. The intraperitoneal injection of TTX alone in dose of3and6μg/kg induced neither a direct LORR action, nor changing of hypnotic action of local anesthetic.Conclution:Systemic application of Local anesthetics drugs Lidocaine, bupivacaine and ropivaine produce general anesthetic effects (hypnotic), and the effect is not directly relative to blocking of sodium channel, therefore, local anesthesia is involved in other mechanism or receptors is to be exploited. Part II:Objective:Systemic administration of local anesthetics has been shown to produce anesthesia sparing effects, our previous studies shows it has hypnotic effects not associated with blocking of sodium channel, although the detail of their actions and mechanisms are under determined. This study investigated the systemic action of local anesthetics and their underlying mechanisms.Methods:Intravenous Lidocaine, have been injected to C57BL/6mice through the tail vein and loss of righting reflex (LORR) was used to evaluate the hypnotic action of these drugs with or without ketamine, sodium channel blocker TTX and NMDA receptor blocker MK-801.Results:Systemic application of local anesthetics lidocaine directly produced hypnotic action with Ec50of15mg/kg, also enhanced the hypnotic action of ketamine, yielding an EC50fraction of ketamine plus lidocaine of1.09, and suggesting that lidocaine and ketamine have additive hypnotic action in mice. Blocking of NMDA receptor by MK-801alone fail to produce hypnosis, however it enhance the LORR of lidocaine with Ec50from15mg/kg to11mg/kg.Conclusions:Local anesthetics produce direct hypnotic actions and potentiate the anesthesia effects for general anesthetic ketamine and this action is not associated with blocking of sodium channel. Blocking of NMDA receptor enhance the hypnotic action of lidocaine.