氯胺酮的临床作用与机制研究进展

Research progress in the mechanisms of the clinical effects of ketamine

氯胺酮是常用的静脉麻醉剂之一,临床应用已超过50年.近年来,针对氯胺酮的药理作用研究取得了多方面的进展.本文从氯胺酮的麻醉作用、镇痛作用、快速抗抑郁作用和副作用等方面简要介绍其临床作用与机制研究的进展.这些进展将从剂量依赖性和靶点广泛性的角度提示一般麻醉剂发挥作用的复杂性.

Ketamine is primarily known as an effective NMDAR （N-methyl-D-aspartic acid receptor） blocker. As one of the intravenous anesthetics, ketamine has been widely used in clinical practice for more than 50 years, exhibiting several different outcomes besides the original anesthetic effects. Recent studies provide insights into the mechanisms of the following neuropharmacological effects of ketamine： （ i ） Anesthesia. The anesthetic effects of ketamine are mainly due to its ability to decrease the inter-cortical communications to generate dissociative anesthesia. Besides the well-known NMDAR, another target for ketamine to show anesthetic effects has been reported to be hyperpolarization-activated cyclic nucleotide-gated channels （HCN channels）. （ii） Analgesia. Ketamine not only exhibits blockade on NMDAR in the central nervous system, but also reverses opioid tolerance when combined with morphine at a low dose. The affinity with sodium and potassium channels makes ketamine possible for analgesia at high doses. However, the clinical analgesic effect is currently controversial, and the algetic cases after the discontinuation of ketamine are probably caused by its metabolic product norketamine. （iii） Anti-depression. Ketamine is recently regarded as a rapid antidepressant drug for its contribution to neurogenesis through several molecular processes, such as the glutamate burst by activating presynaptic NMDAR and AMPAR （α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor）, the synaptic protein synthesis and transportation by activating mTOR （mechanistic target of rapamycin）, and the synaptic maturation by releasing BDNF （brain derived neurotrophic factor）. At the circuit level, ketamine widely reconstructs circuits by dual regulation on NMDAR and AMPAR, and causes loss of phenotype of the PV GABAergic neurons （parvalbumin-positive interneurons）. （iv） Side effects. Ketamine is strictly constrained for its psychiatric side effects resulted from the potent disruption on neural network stability, which shares similar neuro-circuit etiology with schizophrenia. Also, the potential ketamine-induced neuroapoptosis might generate risks for anesthesia during pregnancy and childhood, which is under deep investigation. Due to the potential risks of ketamine, more attention should be paid to the development of novel anesthetics keeping the anesthetic, analgesic and antidepressant effects of ketamine, however, without the potential psychiatric side effects. Thus, exceeding novel knowledge, makes ketamine a representative example for the complexity of anesthetics due to its global targets and dose-dependent properties, which provides a breakthrough point both for the mechanism researches for the working models of general anesthetics and for exploring the state of consciousness of human beings.