Experimental Studies On The NMDA Receptors Involved In The General Anesthesia Of Propofol

Although the precise action of the genera anaesthetics is still not well Understoodsince it's first clinical use 150 years ago. There has been an eXPlosion of Studies over thepast decade on the effects of general anesthetics on putative targets in the central nervoussystem, and show tha they are much more selective than is usually aPpreciated and mayact by binding to on1y a small number of targets. At clinical concentrations these targetsare most likely to be postsynaPtic ligand-gated ion channels, among of which exhibit alarge variance of the sensitivities and specificities. Fdrier characterization of the sites ofthe interaction with anesthetics, as the most importan aspect, the possible relationshipbetween these channels and the producton of general anesthesia are the main poini anddifficulty.Prop o fO l (2, 6 -di is opropylpheno l ) is an intraVenous general anaestheti c s that ischemical1y unrelatCd to other anesthetics. In vitIo Studies showed that a large number ofpostsynaPtic ligand-gated ion channels are sensitive to propofol under it's clinicalconcentrations, including GABAA receptor' NMDA receptOr\ glycine receptor and etc,and GABAA receptor is the moSt sensitive one; therefore, most studies of theunderlying mechanisms ofpropofol anesthesia have focused on GABA ergic neurons, butwhether it's the cnaia1 target of propofol is still controversal. Till now Less work hasbeen carried out on the effects of propofol on excitatory amino acid synaptic transmission,NMDA receptor is the best characterized excitatory neurotransmitter-gated receptOr inmammalian brain, and also has sensitivity to Propofol; however, there have beensurprisingly few reliable modem studies about possible effects of propofol on NMDAreceptor. hi the present experiment, we exaxnined the possible roles of NMDA recePtorplaying in the activities of general anesthesia ofpropofol with in vivo and in vitro studies,and also compared with those of GABAA receptor.And the main resu1ts as follows:(1) In vivo behavioral stUdies: Anesthetic potency were assessed after pretreatffientwith competitive antagonist of NMDA receptor MK-801(0.3~3mg/kg) and GABAAreceptor bicuculline(0.6~6mg/kg) in Kunming mice using the righting reflex, the resultsshowed that MK-80l(0.3~3mg/kg) increased the anesthetic potency of propofol in dose-dependent manner, While this phenomenon was observed only in large dose ofbicuculline(6mg/kg). It referred that propofol anesthesia may be mediated in part by bothreceptors,and pallicularly by the NMDA receptor.(2)In vivo electrophysiological recording: We established the model of extrcellularrecording of a single neuron in the hippocampal CAl area in intact awake rat.Three tyPesof neurons were recorded in the CA1 area, namely nociceptive excitatory neurons,nociceptive inhibitory neurons and nociceptive unrelated neurons. Intravenous injectionof propofol markedly lowered the discharge frequency of the nociceptive excitatoryneurons, while significantly increased that of nocicePtive inhibitory neurons, and tonociceptive unrelated neurons, the responses were quite uncertain. Half effeCtive dose ofthe inhibition of propofol on the nocicePtive excitatory neurons was l .102mg/kg.and inthe presence of NMDA receptor antagonist (MK-801) and GABAA receptor anagonist(bicuculline), the inhibitory actions of propofol (2mg/kg) were both partially anagonized,but with different pattems. As in septo-hippocampal system, microinjection ofpropofol(60ng) can effectively inhibit the discharge activity of nocicePtive excitatoryneurons in CA1 area. As to the inhibition of propofOl on nociceptive excitatory neurons,pre-microinjection of the NMDA receptor antagonist MK-80l and GABAA anagonistbicuculline into medial sepato nucleus affected the inhibitory effect of propofol onneurons in CAl area.(3)In vitro whole cell current recordings f The effects of propofol(2,6diisopropylphenol) on the responses to glutamate and N-...