Nat Neurosci . . . Anesthetic analgesic mechanism: Central amygdala (CeA) anaesthetic neuron cluster.

The main function of anesthesia is to make patients lose pain and consciousness, so as to facilitate the smooth implementation of clinical operation.but not all operations require the patient to be unconscious. For example, the use of low-dose ketamine (ketamine, one of the commonly used clinical anesthetics), can play an analgesic role, but will not cause loss of consciousness, which indicates that anesthesia induced pain loss and loss of consciousness may be through two different pathways.the analgesic mechanism of anesthetics is thought to be through blocking the transmission of peripheral noxious stimulation in the dorsal horn of the spinal cord. However, patients given low-dose anesthetics can still perceive external stimuli while losing pain, which indicates that the analgesic effect of anesthetics comes from higher-level central control.however, the advanced regulatory center of anesthesia and analgesia is still unknown.on May 18, 2020, Professor Fan Wang of Duke University School of Medicine published the latest research results entitled "general anesthetics activate a potential central pain suppression circuit in the amygdala" online on Nature Neuroscience, GA) specifically activates a group of special neurons (ceaga) in the central amygdala (CEA), and this group of ceaga neurons plays an effective analgesic effect by inhibiting multiple downstream pain information processing brain regions.by c-fos staining, the study group found that isoflurane or ketamine induced general anesthesia could significantly activate CEA neurons (ceaga neurons). The anesthetic activated neurons of another brain region (son) found in the study group were mainly involved in the sedative effect of anesthesia, which was published in nerve "a common neuroendocrine substrata for different" General Anesthetics and Sleep” ) 。further immunohistochemistry and in situ hybridization showed that ceaga neurons were all inhibitory GABAergic neurons, and partially expressed pre enkephalin (penk1) or / and protein kinase C (PKC) - [delta] (pkc-d), which indicated that ceaga neurons gathered many types of neurons.the research group used the c-fos neurovirus labeling technology (can), It was published in neuron "capturing and manipulating activated neural assemblies with can delinates a physiological social fear circuit", which can specifically label and regulate ceaga neurons by combining transgenic fostva animals and can lentivirus related viruses.through this method, the researchers found that isoflurane / ketamine / dexmedetomidine with different mechanisms of action can activate the same group of ceaga neurons. In order to further verify this phenomenon and explore the activity characteristics of ceaga neurons during anesthesia, the study group found that most of ceaga neurons increased activity during isoflurane or ketamine anesthesia There were two firing patterns: ISO. / ket. - transient neurons and ISO. / ket. - sustained neurons.at the same time, the same cell tracking analysis was used to further verify that different anesthetics isoflurane / ketamine activated the same group of ceaga neurons.in order to explore the role of ceaga neurons in anesthesia, the research group used photogenetics to specifically regulate ceaga neurons. It was found that activation of ceaga neurons could reduce the mechanical / cold / heat stimuli of animals to acute noxious stimuli, Meanwhile, in formalin induced inflammatory pain model, activation of ceaga neurons can effectively reduce pain handling behavior (licking / wiping); activation of ceaga neurons not only has analgesic effect in acute pain, but also has therapeutic effect on hyperalgesia caused by chronic pain.it is worth noting that under normal conditions, the spontaneous physiological activity of most ceaga neurons does not respond to acute noxious stimuli.at the same time, regulating the activity of ceaga neurons does not cause fear or anxiety like behavior, nor does it affect the mating or sleeping state of animals. This further indicates that ceaga neurons mainly play an analgesic role, and the analgesic effect may be related to internal state rather than external stimulation.how does ceaga neurons play an analgesic role? The study group found that ceaga neurons widely projected to most of the brain regions involved in pain processing by forward whole brain tracing.in formalin inflammatory pain model, the neurons in the downstream brain areas projected by ceaga neurons were significantly activated, while activation of ceaga neurons at the same time could effectively inhibit the neuronal activity in these downstream brain regions, thus playing an analgesic role.in order to further verify the hypothesis that the analgesic effect of anesthesia is independent of sedation, the research group found that the use of low-dose ketamine (animals are still awake) can effectively reduce the pain response caused by capsaicin, while inhibition of ceaga neurons reverses the analgesic effect of low-dose ketamine.at the same time, the study group used calcium imaging recording and the same cell tracking analysis method, and found that normal dose and low-dose anesthetics (isoflurane and ketamine) can activate the same group of ceaga neurons, and a larger proportion of ceaga neurons are continuously activated (ISO. / ket. - maintained neurons) during low-dose anesthesia.it is suggested that ceaga neurons are mainly involved in the analgesic effect of anesthetics rather than sedation.this study indicates that endogenous ceaga neuronal analgesia system can be used as a potential and effective therapeutic target for chronic pain relief.in this paper, Dr. Thuy Hua and Dr. Bin Chen are co first authors, and Professor Fan Wang and Dr. Thuy Hua are co authors.original link: